Benzimidazole derivatives

ABSTRACT

Disclosed are compounds represented by the following chemical formula (I) and pharmacologically acceptable salts thereof which are novel compounds useful as anticancer agents, antiviral agents or antimicrobial agents. ##STR1##

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel benzimidazole derivatives bondable toDNAs to inhibit proliferation of cells, and also to pharmaceuticalcompositions containing same, especially their use as anticancer agents,antiviral agents, antimicrobial agents or the like.

2. Description of the Related Art

DNA-acting compounds include those useful as anticancer agents. Forexample, adriamycin is useful as an anticancer agent which intercalatesinto DNA. Further, DNA-reacting compounds such as cisplatin andmitomycin are also employed widely. Anticancer effects which are derivedfrom such action on DNA are considered to have been ascertained althoughtheir mechanisms have not been fully elucidated. In the meantime, it hascome to be known that distamycin and netropsin are substances bondableto DNA and having anti-tumor activities (Nature, 203, 1064-65(1964)).These substances have attracted attention as groove binders which aredifferent in their manner of bonding with DNA compared to conventionalanticancer agents.

According to the conventional knowledge of anticancer agents, it ispresently by no means possible to foresee which structural part of acompound is really needed for interaction with DNA or what otherstructures can substitute for the part of the compound. It is howevermeaningful to predict the presence of other compounds having a desiredstructure and to make a search for them. A strong demand is thereforebelieved to exist for the search of such a new structure so that a novelanticancer agent can be created.

Also known are compounds in which the structure of an alkylating agenthas been bonded to distamycin derivatives. Typical examples are foundinter alia in J. Am. Chem. Soc., 107, 8266(1985), EP 246868, WO93-13739, J. Med. Chem., 32, 774(1989). Compounds in each of which thestructure of an alkylating agent has been bound to a compound similar todistamycin by bonding N-methyl-imidazole as a partial structure via anamide bond are also known (U.S. Pat. No. 5,273,991). These compoundsinclude those making use of a bis(2-chloroethyl)amino residual group asan alkylating agent. This residual group is already known to be astructural part of anticancer agents. For example, chlorambucil is knownas an anticancer agent which contains a bis(2-chloroethyl)amino residualgroup in its molecule. The anticancer activities of this compound arepresumed to result from alkylation of DNA, enzymes or the like. Howeverthe value of addition of the structure of an alkylating agent, forexample, the structure of chloroethylamine, as a part of the structureof a DNA-bonding anticancer agent is still hardly considered to havebeen ascertained.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel compound whichacts on DNA or contains a structural part capable of acting on DNA andwhich is useful as an anticancer agent, an antiviral agent, anantimicrobial agent or the like.

The above-described distamycin is a typical example of compounds whichbind to DNA. Distamycin is characterized in that a pyrrole ring isbonded via an amide bond. As DNA-binding compounds include several othertypes of compounds, the present inventors made a search for a newstructure under the assumption of existence of compounds which have astructure different from the known compounds and exhibit anticanceraction. As a result, novel compounds having the structure created fromthe direct bonding of a 5-membered aromatic ring with benzimidazole havebeen chosen as compounds useful as anticancer agents. Preferred examplesinclude 1H-2-1-methyl-(substituted)pyrrol-2-yl!benzimidazole-5-carboxamidederivatives, 1H-2- (substituted)pyrrol-2-yl!benzimidazole-5-carboxamidederivatives, 1H-2-(substituted)imidazol-2-yl!benzimidazole-5-carboxamide derivatives,1H-2- 1-methyl-(substituted)imidazol-2-yl!benzimidazole-5-carboxamidederivatives, 1H-2- (substituted)furan-2-yl!benzimidazole-5-carboxamidederivatives, 1H-2-(substituted)thiophen-2-yl!benzimidazole-5-carboxamide derivatives and1H-2- (substituted)thiophen-3-yl!benzimidazole-5-carboxamidederivatives. These compounds have novel structures and are not known atall as useful anticancer agents. These compounds, for example,1H-2-(4-formyl-1-methyl-pyrrol-2-yl)benzimidazol-5-N-(2-amidinoethyl)!-carboxamide have been found to bind to DNA,indicated by the measurement of an increased Tm value (Tm: the meltingtemperature of double-stranded DNA) and, when tested in vitro, showed asimilar degree of proliferation-inhibiting activity against tumor cellsas distamycin.

Compounds in which structure of an alkylating agent has been bonded todistamycin derivatives are known so that there is the chance that theiractivities as anticancer agents may be enhanced by the addition of analkylating moiety. In this regard, an investigation was also conductedat the same time. Compounds containing chlorambucil or anotheralkylating partial structure showed much higher anticancer activitiesthan distamycin or chlorambucil. From this, the compound having astructure in which an aromatic 5-membered ring is bound directly tobenzimidazole has been found to provide a highly active anticancer agentwhen an alkylating agent is added into the same molecule.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The present invention therefore provides a compound represented by thefollowing chemical formula (1) or a pharmacologically acceptable saltthereof: ##STR2## wherein X, Y and Z each independently means CH, N, NH,N(CH₂)_(t) CH₃, S or O with the proviso that X, Y and Z do not have thesame meaning at the same time and t stands for an integer of 0-5, m andn are integers of 0-5, R₁ and R₂ each independently means a hydrogenatom, a C₁₋₂₀ alkyl group, a C₁₋₁₀ haloalkyl group, a C₁₋₁₀ alkoxylgroup, an oxyethylene group, an ethyleneimino group, a hydroxyl group, aC₁₋₁₀ alkylthio group, a substituted or unsubstituted amino group, asubstituted or unsubstituted ammonium group, a substituted orunsubstituted sulfonium group, a substituted or un substituted phenylgroup, a substituted or unsubstituted 5-membered heteroring, asubstituted or unsubstituted 6-membered heteroring, a substituted orunsubstituted fused heteroring, a substituted or unsubstituted amidinogroup, a substituted or unsubstituted guanidino group, an amino acidresidual group, or a group represented by the following chemical formula(2): ##STR3## wherein R₃ means (CH₂)_(r) or (CH₂)_(r) O in which rstands for an integer of 0-5 and the O atom is located closer to thephenyl group, R₄ means a hydrogen atom, a C₁₋₁₀ alkyl group, a C₁₋₁₀alkoxyl group, a halogen atom, a trifluoromethyl group, a cyano group,an amidino group, a guanidino group, a carboxyl group or --COR₇ in whichR₇ means a C₁₋₅ alkyl group, an alkylamino group which may besubstituted by a substituted amino group, an amino group which may besubstituted by a substituted or unsubstituted phenyl group or asubstituted or unsubstituted benzylamino group, R₅ means a hydrogenatom, a C₁₋₁₀ alkyl group, a C₁₋₁₀ alkoxyl group, a halogen atom, or--(CH₂)_(p) N(R₈)₂ or --(CH₂)_(p) NR₈ R₉ in which p stands for aninteger of 0-5, or R₄ and R₅ may form a ring when R₄ and R₅ takemutually adjacent positions, R₆ means a hydrogen atom, --(CH₂)_(p)N(R₈)₂ -- or --(CH₂)_(p) NR₈ R₉ wherein in each case of R₅ and R₆, R₈means --CH₂ CH₂ W, R₉ means a C₁₋₅ alkyl group or a mesyl group, W meansa halogen atom, a hydroxyl group, a mesyloxy group, a tosyloxy group or--OCOR₇ in which R₇ and p have the same meanings as defined above.

The present invention will hereinafter be described in further detail.

Desired examples of the 5-membered ring which contains X, Y and Z in thecompound of the chemical formula (1) include pyrrole, 1-methylpyrrole,imidazole, 1-methylimidazole, furan, thiophene, oxazole, isooxazole,pyrazole and isothiazole.

Preferred examples of the C₁₋₂₀ alkyl group represented by R₁ or R₂include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl and stearyl.

Desired examples of the C₁₋₁₀ haloalkyl group include chloromethyl,chloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorohexyl,chloroheptyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl,bromopentyl, bromohexyl and bromoheptyl.

The substituted or unsubstituted amino group can desirably be an aminogroup or a monoalkylamino or dialkylamino group which has beensubstituted by a linear or branched C₁₋₁₀ alkyl group. Desired examplesinclude methylamino, ethylamino, n-propylamino, i-propylamino,n-butylamino, dimethylamino, diethylamino, dipropylamino anddiisopropylamino groups.

Desired examples of the C₁₋₁₀ alkoxyl group include methoxyl, ethoxyl,n-propyloxy, i-propyloxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy,n-hexyloxy, n-heptyloxy and n-octyloxy.

Desired examples of the C₁₋₁₀ alkylthio group include methylthio,ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio,t-butylthio, n-pentylthio, n-hexylthio, n-heptylthio and n-octylthio.

The substituted or unsubstituted ammonium group can be atrialkylammonium group which has been substituted by a linear orbranched C₁₋₄ alkyl group, for example, trimethylammonium ortriethylammonium, or an ammonium group represented by the chemicalformula (9). In the formula (9), U⁻ can be any anion insofar as theanion is pharmacologically acceptable (for example, Cl⁻, I⁻, OSO₃ ⁻, NO₃⁻, HOOCCH═CHCOO⁻ or the like). R₁₁ and R₁₂ independently mean a linearor branched C₁₋₁₀ alkyl group with methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl beingdesired. ##STR4##

The terms "substituted or unsubstituted sulfonium group" means asulfonium group; or a sulfonium group substituted by a linear orbranched C₁₋₄ alkyl group, for example, a dimethylsulfonium,diethylsulfonium, methylethylsulfonium, methylpropylsulfonium,diisopropylsulfonium or methylisopropylsulfonium group, or a sulfoniumgroup represented by the following formula (10). In the formula (10), U⁻can be any anion insofar as the anion is pharmacologically acceptable(for example, Cl⁻, I⁻, OSO₃ ⁻, NO₃ ⁻, HOOCCH═CHCOO⁻ or the like). R₁₁means a linear or branched C₁₋₁₀ alkyl group with methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl,n-heptyl or n-octyl being desired.: ##STR5##

Illustrative of the substituted or unsubstituted phenyl group include aphenyl group which may be substituted by a halogen atom (fluorine atom,chlorine atom, bromine atom or iodine atom), a linear or branched C₁₋₅alkyl group, a linear or branched C₁₋₅ alkoxyl group, a C₁₋₃alkoxycarbonyl group, a C₁₋₃ haloalkyl group, a cyano group, an amidinogroup, and a C₁₋₃ dialkylamino group. Desired examples of thesubstituted or unsubstituted phenyl group include chlorophenyl,dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl,tribromophenyl, fluorophenyl, difluorophenyl, trifluorophenyl,methylphenyl, ethylphenyl, n-propylphenyl, i-propylphenyl,n-butylphenyl, i-butylphenyl, t-butylphenyl, methoxyphenyl,ethoxyphenyl, methoxycarbonylphenyl, methylcarboxyphenyl,trifluoromethylphenyl, cyanophenyl, amidinophenyl, dimethylaminophenyl,dimethylaminophenyl, and 3,4,5-trimethoxyphenyl. The substitutingposition of each of the above substituents can be the 2-, 3- or4-position in the case of the mono-substitution, any two of the 2-, 3-,4-, 5- and 6-positions in the di-substitution and any three of the 2-,3-, 4-, 5- and 6- positions in the tri-substitution unless otherwisespecifically indicated.

Desired examples of the 5-membered heteroring of the substituted orunsubstituted 5-membered heteroring include pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, pyrazolyl, thiazolyl, isothiazolyl, isooxazolyl,pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, furazanyl,tetrahydrofuranyl, triazolyl and tetrazolyl.

Desired examples of the 6-membered heteroring of the substituted orunsubstituted 6-membered heteroring include pyridyl, pyrimidinyl,pyranyl, pyradinyl, pyridazinyl, piperidyl, piperidinyl, piperazinyl,thiomorpholino, 4-methyl-1-piperazino, 4-benzyl-1-piperazino,1-morpholino, 1-piperidino, 4-piperidino, and 4-methyl-1-piperidino.

Desired examples of the fused heteroring of the substituted orunsubstituted fused heteroring include quinolyl, isoquinolyl, indolyl,isoindolyl, phthalazinyl, quinoxalyl, quinazolyl, cinnolyl, indolinyl,isoindolinyl, carbazolyl, acridinyl, benzotriazolyl, benzisooxazolyl,azaindolyl, azabenzindolyl, benzodioxanyl, piperinyl, and xanthenyl.

In the substituted or unsubstituted 5-membered heteroring, thesubstituted or unsubstituted 6-membered heteroring, or the substitutedor unsubstituted fused heteroring, examples of substituents indicated bythe term "substituted" include halogen atoms (fluorine atom, chlorineatom, bromine atom and iodine atom), linear or branched C₁₋₅ alkylgroups, linear or branched C₁₋₅ alkoxyl groups, C₁₋₃ alkoxycarbonylgroups, C₁₋₃ haloalkyl groups, a cyano group, an amidino group, and C₁₋₃dialkylamino groups.

The substituted or unsubstituted amidino group can desirably be a grouprepresented by the chemical formula (11). R₁₁ means a C₁₋₁₀ alkyl groupwith methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,n-pentyl, n-hexyl, n-heptyl or n-octyl being desired. ##STR6##

The substituted or unsubstituted guanidino group can desirably be agroup represented by the chemical formula (12). R₁₁ means a C₁₋₁₀ alkylgroup with methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,n-pentyl, n-hexyl, n-heptyl or n-octyl being desired. ##STR7##

The term "amino acid residual group" means a carboxyl-removed moiety ofan amino group and desired examples of the amino acid include arginine,histidine and lysine.

The term "halogen atom" as R₄, R₆ and R₇ means F, Cl, Br or I.

Desired examples of the halogen atom as W are Cl and Br.

Preferred examples of the C₁₋₁₀ alkyl group represented by R₅ includemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl,n-hexyl, n-heptyl and n-octyl groups.

Desired examples of the C₁₋₁₀ alkoxyl group represented by R₅ includemethoxy, ethoxy, n-propyloxy, i-propyloxy, n-butoxy, i-butoxy, t-butoxy,n-pentyloxy, n-hexyloxy, n-heptyloxy and n-octyloxy.

When R₄ and R₅ take mutually adjacent positions and form a ring, thering can desirably be represented by the following formula (13):##STR8##

Desired examples of the alkylamino group which is represented by R₇ andmay be substituted by a substituted amino group includedimethylaminoethylamino, dimethylaminopropylamino,dimethylaminobutylamino, diethylaminoethylamino,diethylaminopropylamino, diethylaminobutylamino,dipropylaminoethylamino, dipropylaminopropylamino,dipropylaminobutylamino, diisopropylaminoethylamino,diisopropylaminopropylamino and diisopropylaminobutylamino.

The amino group which is represented by R₇ and may be substituted by asubstituted or unsubstituted phenyl group can desirably be aniline,4-dimethyl-aminoaniline or 4-chloroaniline.

The substituted or unsubstituted benzylamino group represented by R₇ candesirably be benzylamine or 4-dimethylaminobenzylamine.

The term "pharmacologically acceptable salt" means an inorganic acidsalt or an organic acid salt such as the hydrochloride, sulfate,nitrate, acetate, fumarate, maleate, citrate or oxalate.

BEST MODES FOR CARRYING OUT THE INVENTION

A group of compounds, which can be represented by the chemical formula(1), will hereinafter be described by dividing them into the followingthree groups A, B and C.

Incidentally, compound numbers which appear in this specificationindicate the numbers of compounds shown in Tables 1-4.

Group A: Among the compounds represented by the chemical formula (1),those not classified to Group B or Group C and pharmacologicallyacceptable salts thereof.

Group B: Among the compounds represented by the chemical formula (1),the compounds in which R₂ is an oxoethylene group, an ethyleneiminogroup, a halogen-substituted C₁₋₁₀ alkyl group or a group represented bythe formula (2), and pharmacologically acceptable salts thereof.

Group C: Among the compounds represented by the chemical formula (1),the compounds in which R₁ and R₂ are individually a group represented bythe formula (2), and pharmacologically acceptable salts thereof.

A description will next be made of syntheses of these compounds. In thefollowing description and Examples, DCC stands forN,N'-dicyclohexylcarbodiimide, CDI for N,N'-carbonyldiimidazole, HOSufor N-hydroxysuccinimide, EDCI for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DECP fordiethyl cyanophosphonate, HOBt for 1-hydroxybenzotriazole, DMAP for4-dimethylaminopyridine, DMF for dimethylformamide, THF fortetrahydrofuran, DMSO for dimethylsulfoxide, and IPA for isopropanol.Pd/C indicates Pd on charcoal, in which the palladium generally accountsfor 5 to 10%.

A description will now be made of a process for the synthesis of thecompound represented by the chemical formula (3), which is a principalintermediate.

As will be shown below by Reaction scheme (1), the aldehyde of theformula (5) and the 3,4-diaminobenzoic acid of the formula (6) or itsester are heated in nitrobenzene at 100° C. to a reflux temperature,preferably at 130° to 200° C., the reaction mixture is allowed to cooldown to room temperature, and the reaction product of the formula (3),that is, 1H-2-benzimidazole-5-carboxylic acid or its ester derivativecan then be collected by filtration. As will be shown below by Reactionscheme (2), when the ester is obtained here, hydrolysis of it canprovide the corresponding 1H-2-benzimidazole-5-carboxylic acidderivative represented by the chemical formula (14). Although noparticular limitation is imposed on the amounts of the aldehyde of theformula (5) and the 3,4-diaminobenzoate of the formula (6), the lattermay be reacted generally in an amount of 80-120 mole parts per 100 moleparts of the former. The reaction in nitrobenzene is carried out underheat until the raw materials are used up while the progress of thereaction is observed. A heating time in a range of 5-100 hours can bringabout good results. The heating can be conducted continuously orintermittently until the total heating time reaches the above-describedtime. The hydrolysis of the ester can be conducted by heating it in amixed solvent of water and ethanol or water and methanol while usingsodium hydroxide or potassium hydroxide. Although the proportion ofwater in the mixed solvent can be from 5 to 90 wt. %, 40 to 60 wt. % cangive good results. The heating temperature can range from 50° C. to thereflux temperature. ##STR9##

For example, selection of 1-methyl-4-nitropyrrole-2-carboxyaldehyde,4-nitropyrrole-2-carboxyaldehyde, 5-nitropyrrole-2-carboxyaldehyde,1-methyl-4-nitroimidazole-2-carboxyaldehyde,4-nitroimidazole-2-carboxyaldehyde, 5-nitrofuran-2-carboxyaldehyde,4-nitrothiophene-2-carboxyaldehyde and2-nitrothiophene-4-carboxyaldehyde as starting materials makes itpossible to synthesize, by similar procedures, 1H-2-1-methyl-4-nitropyrrol-2-yl!benzimidazole-5-carboxylic acid, 1H-2-4-nitropyrrol-2-yl!benzimidazole-5-carboxylic acid, 1H-2-5-nitropyrrol-2-yl!benzimidazol-5-carboxylic acid, 1H-2-1-methyl-4-nitroimidazol-2-yl!benzimidazole-5-carboxylic acid, 1H-2-4-nitroimidazol-2-yl!benzimidazole-5-carboxylic acid, 1H-2-5-nitrofuran-2-yl!benzimidazole-5-carboxylic acid, 1H-2-4-nitrothiophen-2-yl!benzimidazole-5-carboxylic acid and 1H-2-2-nitrothiophen-4-yl!benzimidazole-5-carboxylic acid, respectively.

Incidentally, to heat a substituted benzaldehyde and 3,4-diaminobenzoicacid in nitrobenzene for the preparation of a corresponding1H-2-phenylbenzimidazole has already been disclosed in Syn. Commun., 20,955-963(1990). Use of the above-described aromatic 5-membered aldehydederivatives having a nitro group is however novel.

As a further alternative, the compound of the formula (14) can also besynthesized as will be described next. For example,1-methyl-4-nitro-2-pyrrolecarboxylic acid is reacted, by using theprocess disclosed in Tetrahedron, 34, 2389-2391(1978), with thionylchloride into 1-methyl-4-nitro-2-pyrrolecarboxylic acid chloride, whichis then reacted with a 3,4-diaminobenzoic acid to obtain3-amino-4-(1-methyl-4-nitro-2-pyrrolecarboxamido)benzoic acid or4-amino-3-(1-methyl-4-nitro-2-pyrrolecarboxamido)benzoic acid as theexemplified compound. Here, the reaction product can also be a mixtureof both the benzoic acids. Methylene chloride, chloroform, DMF or thelike can be used as a solvent. Other solvents are also usable as long asthey do not take part in the reactions. Heating of the thus-obtainedamide compound with trilfluoroacetic acid with any solvent, which do notparticipate in the reaction, provides1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid.Further, 1-methyl-4-nitro-2-trichloroacetylpyrrole which is a knowncompound disclosed in Heterocycles, 27, 1945-1952(1988) is likewisereacted with 3,4-diaminobenzoic acid to obtain3-amino-4-(1-methyl-4-nitro-2-pyrrolecarboxamido)-benzoic acid or4-amino-3-(1-methyl-4-nitro-2-pyrrolecarboxamido)benzoic acid. Here, thereaction product can also be a mixture of both the benzoic acids. Thereaction product can also be converted into1H-2-(1-methyl-4-nitropyrrole-2-yl)benzimidazole-5-carboxylic acidlikewise. The reaction can also be conducted similarly by using as astarting material an equivalent carboxylic acid other than1-methylpyrrole-2-carboxylic acid.

The above-described reactions can be summarized as follows (Reactionscheme (3)): ##STR10##

A description will next be made of the syntheses of the compounds in therespective groups.

As will be shown below in Reaction scheme (4), syntheses of thecompounds in Group A can be conducted generally by uniting an aminocompound, which is represented by the formula (20) and generallycontains the moiety designated by R₂, with the carboxylic acid of theformula (14) in the presence of a suitable condensing agent, forexample, DCC, CDI, EDCI, DECP or the like, subjecting the so-obtainedintermediate of the formula (21) to catalytic hydrogenation to reduceits nitro group into an amino compound and then, reacting a carbonylcompound containing the moiety designated by R₁ to the resultant aminocompound. ##STR11##

The amino compound which is represented by the formula (20) and containsthe moiety designated by R₂ can be either one available as a reagent orone synthesizable through several steps by combining known reactions.Usable amino compounds include alkylamino compounds, for example,methylamine, ethylamine, 1-aminopropane, 2-aminopropane, 1-aminobutaneand 2-aminobutane. Examples of substituted amino compounds includedimethylaminopropylamine, diethylaminopropylamine anddipropylaminopropylamine. Examples of amino compounds using as asubstituent an alkylthio group include methylthiopropylamine,ethylthiopropylamine, propylthiopropylamine, butylthiopropylamine andthe like. Examples of amino compounds using as the substituent anammonium group include aminopropyl-trimethylammonium,aminopropyltriethylammonium and the like. When amino-containingderivatives substituted by the substituted or unsubstituted phenylgroup, the substituted or unsubstituted 5-membered heteroring, thesubstituted or unsubstituted 6-membered heteroring and the substitutedor unsubstituted fused heteroring are used in the reaction, compoundswhich contain, as a substituent represented by R₂, the substituted orunsubstituted phenyl group, substituted or unsubstituted 5-memberedheteroring, substituted or unsubstituted 6-membered heteroring andsubstituted or unsubstituted fused heteroring can be synthesized,respectively. Upon uniting these amino compounds with the carboxylicacid of the formula (14) by using a suitable condensing agent, forexample, DCC, CDI, EDCI, DECP or the like, an ordinary solvent can beused as a reaction solvent. DMF or a mixed solvent containing DMF canhowever provide relatively good results. The reaction temperature maypreferably range from -5° C. to 30° C. The reaction is allowed toproceed while observing its progress. The reaction time generally rangesfrom 1 hour to 50 hours.

Synthesis of compounds which contain an amidino group as R₂ can beconducted as will be described below. As will be shown below in Reactionscheme (5), the compound of the formula (14) (e.g.,1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid; otherintermediates are treated similarly) and 3-amino-propionitrile are firstunited together. At this time, a general condensing agent such as DCC,CDI, EDCI or DECP can be used. It is also possible to add HOBt or HOSuto DCC. The reaction can desirably be conducted at 0°-30° C. Thereaction mixture is suspended in ethanol, followed by bubbling ofhydrogen chloride gas, so that the crystals so formed are collected byfiltration. The crystals are then dissolved or suspended in a solvent.Ammonia gas is bubbled through the resulting solution or suspension,whereby the target amidino compound (e.g.,1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide; this applies equally to otherintermediates) is obtained. As a reaction solvent for the abovereaction, ethanol or a mixed solvent of ethanol and methanol is desired.The proportion of ethanol can be freely chosen in a range of 10-100%.##STR12##

Reactions with amines such as methylamine and ethylamine instead of thebubbling of ammonia gas provide substituted amidino compounds,respectively, as shown in Reaction scheme (6): ##STR13##

The above-described reactions shown in Reaction schemes (4)-(6) can beconducted using, as a precursor, the compound of the formula (14).Specific examples of the compound include 1H-2-1-methyl-(nitro-substituted) pyrrol-2-yl!benzimidazole-5-carboxylicacid, 1H-2- (nitro-substituted)pyrrol-2-yl!benzimidazole-5-carboxylicacid, 1H-2-1-methyl-(nitro-substituted)imidazol-2-yl!benzimidazole-5-carboxylicacid, 1H-2- (nitro-substituted)imidazol-2-yl!benzimidazole-5-carboxylicacid, 1H-2- (nitro-substituted)-furan-2-yl!benzimidazole-5-carboxylicacid, 1H-2- (nitro-substituted)thiophen-2-yl!benzimidazole-5-carboxylicacid, or 1H-2-(nitro-substituted)thiophene-4-yl!benzimidazole-5-carboxylic acid.

A description will next be made of a method for synthesizing the sidechain corresponding to R₁.

First, the synthesis of, as a side chain corresponding to R₁, thesubstituent represented by the formula (2) will be described. As anitro-containing carboxylic acid derivative to be used in the synthesis,a compound which can be synthesized by using a commercially-availablereagent or a known reaction can be employed. The nitro-containingcarboxylate ester derivative of the formula (25) in Reaction scheme (7)is reduced into the corresponding amino compound of the formula (26) bycatalytic hydrogenation while using Pd/C as a catalyst. Here, methanol,ethanol, DMF and the like can be used either singly or in combination asa reaction solvent. It is preferred to conduct the reaction at atemperature of 0°-30° C. The reaction time ranges from 30 minutes to 2hours. As shown in the below-described reaction scheme, ethylene oxideis reacted to the amino compound of the formula (26) so formed to obtainthe compound of the formula (27). For this reaction, 10-80% acetic acidcan be used as a reaction solvent. The reaction is conducted at atemperature in a range of from -20° C. to 50° C. The reaction time maypreferably range from 1 hour to 50 hours. The compound of the formula(27) is then chlorinated with an appropriate chlorinating agent such asthionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorusoxychloride, mesyl chloride (in DMF), a combination of mesyl chlorideand sodium chloride, a combination of mesyl chloride and lithiumchloride, dichlorotriphenylphosphoran, or the like, whereby the compoundof the formula (28) can be obtained by changing OH group into Ci⁻radical. The reaction can be conducted at 0°-100° C. and the reactiontime can range from 20 minutes to 5 hours. An ordinary solvent such aschloroform, benzene or toluene can be used as a reaction solvent.Further, DMF can be mixed with these solvents. In the case of thionylchloride or oxalyl chloride, on the other hand, the reaction can beconducted in a solventless manner. The compound represented by theformula (28) is subjected to hydrolysis with an acid to obtain acarboxylic acid derivative of the formula (29). This can be achieved,for example, by heating the compound at 80° C. to the reflux temperaturein the presence of concentrated hydrochloric acid. Desired reaction timeis 30 minutes to 5 hours. ##STR14##

Side chains other than those described above can be prepared by usingcommercially-available reagents or conducting known reactions in severalsteps.

For example, the compound of the formula (7) and the compound of theformula (29) can be united using an appropriate condensing agent such asDCC, CDI, EDCI, DECP or the like. An ordinary solvent can be used as areaction solvent. DMF or a mixed solvent containing DMF can howeverprovide relatively good results. The reaction temperature may preferablyrange from -5° C. to 30° C. The reaction is allowed to proceed whileobserving its progress. The reaction time generally ranges from 1 hourto 50 hours. Alternatively, after the compound of the formula (29) isconverted to a corresponding acid chloride by using thionyl chloride,oxalyl chloride or the like in an ordinary solvent (ex. methylenechloride, chloroform, toluene, DMF or the like. These solvents can beused either singly or in combination) and the acid chloride so obtainedcan be united with the compound represented by the formula (7). Thereaction temperature may preferably range from -5° C. to 30° C. Thereaction is allowed to proceed while observing its progress. Thereaction time generally ranges from 1 hour to 50 hours. In the abovereactions, the partial structure of R₁ can be united.

A description will next be made of syntheses of the compounds in GroupB.

First, the synthesis of a side chain corresponding to R₂ will bedescribed. A nitro-containing aniline derivative or a nitro-containingaminoalkylbenzene derivative is selected as a starting material. Aderivative containing an appropriate substituent can be obtained byusing a commercially-available reagent or a known reaction, or can alsobe synthesized in accordance with the following manner.

As will be shown below in Reaction scheme (8), the amino compound of theformula (31) is synthesized from the carboxylic acid of the formula (30)in accordance with the process disclosed in J. Med. Chem. 33,3014-3019(1990). Use of this process makes it possible to synthesize amethylene chain derivative in which two or more methylene groups arecontains as R₃. (A substituent corresponding to R6, which will bedescribed next, supposed to have already been introduced to the compoundof the formula (30)) ##STR15##

A description will next be made of the introduction of the moietycorresponding to R₆ to the side chain corresponding to R₂.

The reaction can be generally conducted in accordance with the followingtwo processes:

As is shown in Reaction scheme (9), N,N-bis(hydroxyethyl)amine is firstallowed to act on the halogenated benzene derivative of the formula (32)which contains a nitro group and an appropriate substituent (in theformula (32), a halogen atom is illustrated by F as an example), wherebythe compound of the formula (33) is obtained. Here, DMSO can be used asa reaction solvent. The reaction temperature can range from 20° C. to100° C. The reaction time can preferably range from 10 minutes to 4hours. The chloride of the formula (34) can be obtained by reacting,with the intermediate of the formula (33), an appropriate chlorinatingagent such as thionyl chloride, oxalyl chloride, phosphoruspentachloride, phosphorus oxychloride, mesyl chloride, a combination ofmesyl chloride (in DMF) and sodium chloride or the like. The reactioncan be conducted at 0°-100° C. and the reaction time can range from 20minutes to 5 hours. An ordinary solvent such as chloroform, benzene ortoluene can be used as a reaction solvent. Further, DMF can be mixed tothese solvents. The reaction can also be conducted in a solventlessmanner. ##STR16##

As an alternative, the compound of the formula (36) is obtained byreacting ethylene oxide with the nitro-containing aniline derivative (inthe case of p=0) or the aminoalkylbenzene derivative (in the case that pis 1 or greater), each represented by the formula (35) shown below inReaction scheme (10). For this reaction, 10-80% acetic acid (or asolution of p-toluenesulfonic acid in methanol) can be used as areaction solvent. The reaction is conducted at a temperature in a rangeof from -20° C. to 50° C. The reaction time may preferably range from 1hour to 50 hours. The compound of the formula (36) so obtained ischlorinated by an appropriate chlorinating agent such as thionylchloride, oxalyl chloride, phosphorus pentachloride, phosphorusoxychloride, mesyl chloride (in DMF) or a combination of mesyl chlorideand sodium chloride, whereby the compound of the formula (37) can beobtained. The reaction can be conducted at 0°-100° C. and the reactiontime can range from 20 minutes to 5 hours. An ordinary solvent such aschloroform, benzene or toluene can be used as a reaction solvent.Further, DMF can be mixed to these solvents. In the case of thionylchloride or oxalyl chloride, on the other hand, the reaction can beconducted in a solventless manner. ##STR17##

Upon synthesis of the amino compound from the corresponding nitrobenzenederivative, it is the common practice to conduct the synthesis bycatalytic hydrogenation making use of Pd/C as a catalyst or by areducing reaction making use of tin chloride and hydrochloric acid. As areduction process especially in the case of the above-describednitrobenzene derivative with an N,N-bis(chloroethyl)amino group bondedthereto, the reduction process making use of tin chloride andhydrochloric acid was known widely, for example, as disclosed in J.Chem. Soc. 1972-83(1949) or J. Med. Chem. 33, 112-121(1990). Thisreduction can be effectively conducted in accordance with the followingreaction and the treatment after the reaction can be conducted moreeasily. Namely, a nitro compound as a starting material is dissolved ina suitable solvent, for example, ethanol, methanol, ethyl acetate, THFor DMF, or a mixed solvent of at least two of them. Pd/C is added in anamount equivalent to 0.5-50 wt. % based on the nitro compound, followedby hydrogenation at room temperature under normal pressure so that thecorresponding amino compound is obtained. At this time, hydrochloricacid can also be added in an amount equi-molar to or greater than theamount of the nitro derivative, generally in a molar amount 1 to 1.2times as much as the nitro derivative. The catalyst is removed byfiltration, the solvent is distilled out, and the residue is thentreated by using a suitable solvent, for example, ethanol, IPA or ethylether or a mixed solvent of at least two of them, whereby the targetcompound can be obtained easily in the form of its hydrochloride.

As shown in Reaction scheme (11), the nitro compound of the formula (34)obtained by the above reactions (Reaction schemes (9), (10)) isconverted to the corresponding amino compound of the formula (38) bycatalytic hydrogenation. The nitro compound of the formula (37) can alsobe converted to the corresponding amino compound. Upon conducting thecatalytic hydrogenation, hydrochloric acid can be added in an amountequimolar to or greater than the amount of the nitro derivative,generally in a molar amount 1-1.2 times as much as the nitro derivativeto obtain the corresponding amino compound stably. Desirably, thecatalytic hydrogenation can be conducted at 5°-30° C. An ordinarysolvent is used as a reaction solvent. Desired is, for example, DMF or amixed solvent of DMF and methanol. The proportion of DMF in the mixedsolvent can be chosen from a range of 5-100%, with 20-100% beingdesired. ##STR18##

As shown in the below-described reaction scheme (12), the compound ofthe formula (39) can be obtained by uniting the amino compound obtainedabove and the compound of the formula (14) using an appropriatecondensing agent such as DCC, EDCI, DECP or the like. At this time, anordinary solvent can be used as a reaction solvent. DMF or a mixedsolvent containing DMF can however provide relatively good results. Thereaction temperature may preferably range from -5° C. to 30° C. Thereaction is allowed to proceed while observing its progress. Thereaction time generally ranges from 1 hour to 50 hours. ##STR19##

Similarly, as will be shown below in Reaction scheme (13), the compoundof the formula (40) can be synthesized by uniting the benzimidazolederivative of the formula (14) with the amino compound of the formula(31), which had been obtained in the reduction reaction shown above inReaction scheme (8), using an ordinary condensing agent such as CDI,DECP, DCC, a combination of DCC and HOBt, or the like. DMF is desired asa reaction solvent, although other general solvents can also be used.End of the reaction can be confirmed by proceeding with the reactionwhile checking its progress by TLC or the like. It is desired to bringthe reaction into completion in 1-40 hours. The reaction temperature maydesirably range from -5° C. to 40° C. ##STR20##

In the above reaction scheme, it is possible to treat the compound ofthe formula (39) as the compound of the formula (40) wherein n=0. Thisalso applies to the description until Reaction scheme (19).

As will be shown below in Reaction scheme (14), the nitro group of thecompound of the formula (40) can be reduced into the corresponding aminogroup by conducting catalytic hydrogenation while using Pd/C as acatalyst. The reaction proceeds in a substantially quantitative manner.As a solvent for the above reaction, ethanol, methanol and DMF can beused either singly or in combination. At this time, hydrochloric acidcan be added in an amount equimolar to or greater than the amount of thenitro derivative, generally in an amount 1-1.2 times in moles as much asthe nitro derivative. It is desired to perform the reaction for 10minutes to 20 hours. The desired reaction temperature can range from 0°C. to 40° C. ##STR21##

The above-described bonding of the aniline derivative in Reaction scheme(13) and the subsequent reducing reaction in Reaction scheme (14)constitute a new synthesis route not seen in any publications availableto date. For example, a bonding reaction between a distamycin derivativeand N,N-bis(2-chloroethyl)-1,4-phenylenediamine is found in JapanesePatent Laid-Open No. 92933/1994. In this publication, too, thedistamycin moiety is synthesized in advance and the bonding reaction ofN,N-bis(2-chloroethyl)-1,4-phenylenediamine is conducted at the end.This means that the bonding of the N,N-bis(2-chloroethyl)amino grouphaving chemically high reactivity is deferred until the end. In the meantime, the present inventors have demonstrated that the target compoundcan be obtained at a high yield even when the aniline derivative moietyis introduced beforehand into the molecule in contrast to theabove-described apparently reasonable reaction route.

As will be shown below by Reaction scheme (15), the carboxylic acidderivative of the formula (8) is condensed with the amino compound ofthe formula (41), which had been obtained in the above reductionreaction, using a conventional condensing agent (for example, DCC, CDI,EDCI, DECP or the like), whereby the carboxylic acid derivative can bebonded as the moiety R₁. Although a general solvent can be used in thisreaction, DMF or a mixed solvent containing DMF provides good results.The desired reaction time can range from 30 minutes to 40 hours. It isdesired to conduct the reaction at 020 C. to 40° C. ##STR22##

Use of N,N-dimethylaminopropionic acid, N,N-dimethylaminobutyric acid orthe like as an example of the carboxylic acid derivative permitsintroduction of a substituted amino group into the moiety R₁. Further,use of carboxypropyltrimethylammonium makes it possible to introduce anammonium group into the moiety R₁. Use of methylthiopropionic acid orthe like can introduce an alkylthio group. On the other hand, use of4-amidinobenzoic acid, 3-pyridinecarboxylic acid, 4-piperidinecarboxylicacid, pyrrole-2-carboxylic acid, indole-2-carboxylic acid or the likemakes it possible to introduce a substituted or unsubstituted phenylgroup, a substituted or unsubstituted 5-membered heteroring, asubstituted or unsubstituted 6-membered heteroring or a substituted orunsubstituted fused heteroring.

As will be shown in Reaction scheme (16), for example, 1H-2-4-(3-methylthiopropionylamino)-1-methylpyrrol-2-yl!benzimidazole-5-N- 4-N,N-bis(2-chloroethyl)amino!phenylamino!!carboxamide hydrochloride canbe methylated further as disclosed in J. Org. Chem., 25, 804-807(1960)or methylated by an ordinary methylating agent such as methyliodide,dimethylsulfonic acid or the like to obtain its sulfonium derivative ofthe formula (44). As a reaction solvent, formic acid, acetic acid,methanol or the like can be used. Its desired reaction time can rangefrom 1 hour to 60 hours. It is desired to conduct the reaction at 0° C.to 60° C. ##STR23##

Counter anions (I⁻) of the sulfonium compound obtained above can beconverted to other anions by a known process. For example, counteranions I⁻ can be converted to Cl⁻ by using, for example, an ion exchangeresin ("DOWEX" 1×8, Cl⁻ type).

Likewise, further alkylation of a compound, which has as R₁ an aminogroup substituted by two alkyl groups, makes it possible to obtain anammonium compound.

Further, the compound of the formula (46) can be obtained by reacting apyridine derivative of the formula (45) shown in Reaction scheme (17)with the compound of the formula (41). At this time, the pyridinederivative is first converted into its acid chloride by using anordinary reagent such as thionyl chloride and then united using anordinary base such as triethylamine in an ordinary solvent such asmethylene chloride, chloroform or the like. It is desired to conductreaction at -5° C. to 50° C. The reaction time is preferably ranges from1 hour to 50 hours. Alternatively, the pyridine derivative can becondensed with the compound of the formula (41) by using an appropriatecondensing agent such as DCC, CDI, EDCI, DECP or the like. An ordinarysolvent such as DMF, chloroform, methylene chloride or the like isemployed as a reaction solvent. The reaction is conducted preferably at-5° C. to 50° C. The desired reaction time ranges from 1 hour to 50hours. ##STR24##

As will be described below in Reaction scheme (18), the compound of theformula (47) can be obtained by subjecting the compound of the formula(46) to methylation with methyl iodide. At this time, an ordinarysolvent such as methanol, acetone, chloroform, methylene chloride or thelike is employed. The reaction is preferably conducted at -5° C. to 50°C. The desired reaction time is 1 hour to 50 hours. ##STR25##

As will be shown below in Reaction scheme (19), the compound of theformula (48) with guanidine introduced into R₁ can be synthesized byreacting a guanidinoacetic acid to the amino compound of the formula(41) ##STR26##

This guanidino group can be easily acylated. A reaction with an acidanhydride or an acid chloride makes it possible to introduce asubstituted guanidine derivative into R₁. The reaction temperature canrange from -5° C. to 30° C. As a reaction solvent, ordinary solventssuch as chloroform, benzene, toluene and DMF can be used either singlyor in combination. The reaction time can range from 1 hour to 50 hours.

A cyano-containing carboxylic acid derivative such as 3-cyanopropionicacid is bonded by an ordinary condensing agent (DCC, CDI, EDCI, DECP orthe like). Although an ordinary solvent can be used as a reactionsolvent in the above reaction, DMF or a mixed solvent containing DMFprovides good results. The reaction time can desirably range from 1 hourto 24 hours. The desired reaction temperature can range from 0° C. to40° C. The reaction product can be dissolved in ethanol, followed bybubbling of hydrogen chloride gas (0°-30° C., 20 minutes to 2 hours). Afurther reaction with an amino compound makes it possible to synthesizea substituted or unsubstituted amidino compound. For example, an amidinocompound can be synthesized by reacting ammonium acetate or bubblingammonia gas. Use of methylamine, for example, can synthesize amethyl-substituted amidino compound. As a solvent usable in thisreaction, ethanol, methanol or a mixed solvent thereof can be used. Thedesired reaction time may range from 30 minutes to 24 hours.

Other compounds can be synthesized under the above-described conditionsprovided that the starting materials are changed.

A description will next be made of the compounds in Group C.

As will be shown below in Reaction scheme (20), a compound of theformula (49) is subjected to catalytic hydrogenation at room temperatureunder normal pressure, whereby the compound is reduced into acorresponding amino compound (50). As a solvent for this reaction,ethanol, methanol and DMF can be used either singly or in combination.Here, hydrochloric acid can be added in an amount equimolar to orgreater than the amount of the nitro derivative, generally in a molaramount 1-1.2 times as much as the nitro derivative. The desired reactiontime can range from 10 minutes to 20 hours. It is desired to conduct thereaction at a reaction temperature in a range of from 0° C. to 40° C.Subsequent to the reduction, a carboxylic acid derivative of the formula(51) is reacted with an amino compound of the formula (50) as shown inReaction scheme (21), whereby a compound of the formula (52) can beobtained. At this time, a conventional condensing agent (for example,DCC, CDI, EDCI, DECP or the like) can be used. Although a generalsolvent can be used in this reaction, DMF or a mixed solvent containingDMF provides good results. The desired reaction time can range from 30minutes to 40 hours. It is desired to conduct the reaction at 0° C. to40° C. In essence, this synthesis process is not different from thosedescribed above for groups A and B, and for group C the chemical formula(2) is bonded to the moieties R₁ and R₂. ##STR27##

Examples of the compounds embraced by the formula (1) of the presentinvention will be shown in Tables 1-4. In these tables, counter anionsof the ammonium group or the sulfonium group are not indicated. Anycounter anions can be used insofar as they are recognized aspharmacologically acceptable. When it is necessary to specify thecounter anions, they are described specifically.

The compounds according to the present invention are useful asanticancer agents having excellent activities. Applicable cancersinclude leukemia, osteosarcoma, breast cancer, ovarian cancer, stomachcancer, colon cancer, lung cancer, head and neck cancer, and the like.Further, these compounds can also be used as antibacterial agents andantiviral agents.

Their formulation into dosable preparations can be conducted by methodsknown per se in the art.

As dosage forms, various dosage forms can be chosen depending on theobjects of treatments. Representative dosage forms include solidpreparations, liquid preparations, suppositories, etc. Morespecifically, there are various preparations as will be described next.

These preparations are considered to include, as solid preparations,tablets, pills, powders, granules and capsules; as liquid preparations,injections in the form of solutions, and suspensions, syrups andemulsions; and as other preparations, suppositories and the like.

Upon formation into tablets, a variety of additives well known ascarriers for many years in the present field of art can be used.Illustrative carriers include excipients lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose and silicic acid; binders such as water, ethanol, propanol,simple syrup, glucose solution, starch solution, gelatin solution,shellac solution, methylcellulose solution, hydroxypropylcellulosesolution, polyvinylpyrrolidone solution, and carboxymethylcellulosesolution; disintegrants such as dried starch, sodium arginate, agarpowder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylenesorbitan fatty acid esters, sodium lauryl sulfate, stearicmonoglyceride, starch, and lactose; disintegration inhibitors such assucrose, stearic acid, cacao butter, and hydrogenated oils; absorptionpromoters such as quaternary ammonium salts and lauryl sodium sulfate;moisturizers such as glycerin and starch; adsorbents such as starch,lactose, kaolin, bentonite, colloidal silicic acid, crystallinecellulose, and light anhydrous silicic acid; and lubricants such astalc, stearate salts, boric acid powder, and polyethylene glycol.

In the case of tablets, they can be formed, as needed, into tabletsapplied with a conventional coating, for example, into sugar coatedtablets, gelatin coated tablets, enteric coated tablets or film coatedtablets; or they can be formed into double layer tablets or multiplelayer tablets.

Upon formation into pills, a variety of additives well known as carriersfor many years in the present field of art can be used. Illustrativecarriers include excipients such as glucose, lactose, starch, cacaobutter, hydrogenated vegetable oils, kaolin and talc; binders such asgum arabic powder, tragacanth powder and gelatin; and disintegrants suchas calmerose calcium and agar.

Capsules are formulated generally by mixing a compound of the presentinvention as an active ingredient with one of the above-exemplifiedvarious carriers and then filling the resultant mixture in hard gelatincapsules, soft capsules or the like.

To form as an injection, it is possible to use, upon formation into asolution, emulsion or suspension, a liquid widely employed as a diluentin the present field of art, for example, water, ethanol, macrogol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester, cottonseed oil, corn oil, peanut oil, olive oil or the like. Further, eachcompound of the present invention can be used as a suspension or anemulsion by adding water to the compound and then forming the mixtureinto an aqueous suspension in the presence of an appropriate surfactantor into an emulsion by using a surfactant such as "HCO-60". Further,sodium chloride, glucose or glycerin can be incorporated inpharmaceutical preparations. In addition, an ordinary solubilizer,buffer, smoothing agent or the like can also be added.

Upon forming suppositories, a wide variety of additives conventionallyknown as carriers can be used. Illustrative usable examples of suchadditives include polyethylene glycol, cacao butter, higher alcohols,esters of higher alcohols, gelatin, and semi-synthetic glyceride.

One or more of colorants, preservatives, perfumes, corrigents,sweeteners and other drugs can be incorporated in pharmaceuticalpreparations as needed.

No particular limitation is imposed on the content of each compound ofthe present invention contained as an active ingredient in suchpharmaceutical preparations. Its content can be chosen suitably from awide range. In general, however, it is desired to contain a compound ofthe present invention in an amount of about 1-70 wt. %, preferably about5-50 wt. % in each preparation composition.

No particular limitation is imposed on the manner of administration ofthese pharmaceutical preparations according to the present invention.Each preparation can be administered to a patient in a mannercommensurate with the form of the preparation, the age, sex, otherconditions, the seriousness of disease of the patient. For example,tablets, pills, solutions, suspensions, emulsions, powders, granules,syrups and capsules can be administered orally. Injections can beintravenously administered either singly or as mixtures with an ordinaryfluid replacement such as a glucose solution or an amino acid solution.These injections can also be administered singly by an intramuscular,subcutaneous or intraperitoneal route. Suppositories are rectallyadministered. The dose of each pharmaceutical preparation according tothe present invention can be suitably chosen depending on the manner ofits administration and the age, sex, other conditions and theseriousness of disease of each patient. In general, it is howeverdesired to control the daily dosage at about 0.001-1,000 mg or so interms of the amount of the compound as the active ingredient. Further,the compound as the effective ingredient can desirably be contained in arange of about 0.001-1,000 mg in each preparation which is in the formof a dosage unit.

Generally speaking, an anticancer agent, even in the case of a widelyused drug such as adriamycin or cisplatin, can hardly be considered tohave small side effects. In view of the current level of technology,these side effects should be considered in relation to the strength ofits action. The side effects are therefore unavoidable to some extent.Side effects of each compound according to the present invention are ofsuch level that no problem will arise as long as the compound is used asan anticancer agent.

                                      TABLE 1                                     __________________________________________________________________________    Compd. No.                                                                          R.sub.1                m  R.sub.2     n                                 __________________________________________________________________________     ##STR28##                                                                           ##STR29##             0                                                                                 ##STR30##  2                                 2                                                                                    ##STR31##             1                                                                                 ##STR32##  2                                 3                                                                                    ##STR33##             2                                                                                 ##STR34##  2                                 4                                                                                    ##STR35##             3                                                                                 ##STR36##  2                                 5                                                                                    ##STR37##             0                                                                                 ##STR38##  2                                 6                                                                                    ##STR39##             0                                                                                 ##STR40##  2                                 7                                                                                    ##STR41##             0                                                                                 ##STR42##  2                                 8                                                                                    ##STR43##             0                                                                                 ##STR44##  2                                 9                                                                                    ##STR45##             0                                                                                 ##STR46##  2                                 10                                                                                   ##STR47##             0                                                                                 ##STR48##  2                                 11                                                                                   ##STR49##             0                                                                                 ##STR50##  2                                 12                                                                                   ##STR51##             0                                                                                 ##STR52##  2                                 13                                                                                   ##STR53##             1                                                                                 ##STR54##  2                                 14                                                                                   ##STR55##             0                                                                                 ##STR56##  2                                 15                                                                                   ##STR57##             0                                                                                 ##STR58##  2                                 16    Br                     5                                                                                 ##STR59##  2                                 17                                                                                   ##STR60##             0                                                                                 ##STR61##  2                                 18                                                                                   ##STR62##             1                                                                                 ##STR63##  2                                 19                                                                                   ##STR64##             2                                                                                 ##STR65##  2                                 20                                                                                   ##STR66##             3                                                                                 ##STR67##  2                                 21                                                                                   ##STR68##             0                                                                                 ##STR69##  2                                 22                                                                                   ##STR70##             0                                                                                 ##STR71##  2                                 23                                                                                   ##STR72##             0                                                                                 ##STR73##  2                                 24                                                                                   ##STR74##             0                                                                                 ##STR75##  2                                 25                                                                                   ##STR76##             0                                                                                 ##STR77##  3                                 26                                                                                   ##STR78##             1                                                                                 ##STR79##  3                                 27                                                                                   ##STR80##             2                                                                                 ##STR81##  3                                 28                                                                                   ##STR82##             3                                                                                 ##STR83##  3                                 29                                                                                   ##STR84##             0                                                                                 ##STR85##  3                                 30                                                                                   ##STR86##             0                                                                                 ##STR87##  3                                 31                                                                                   ##STR88##             0                                                                                 ##STR89##  3                                 32                                                                                   ##STR90##             0                                                                                 ##STR91##  3                                 33                                                                                   ##STR92##             0                                                                                 ##STR93##  2                                 34                                                                                   ##STR94##             0                                                                                 ##STR95##  2                                 35                                                                                   ##STR96##             0                                                                                 ##STR97##  2                                 36                                                                                   ##STR98##             0                                                                                 ##STR99##  2                                 37                                                                                   ##STR100##            1                                                                                 ##STR101## 2                                 38                                                                                   ##STR102##            0                                                                                 ##STR103## 2                                 39                                                                                   ##STR104##            0                                                                                 ##STR105## 2                                 40    Br                     5                                                                                 ##STR106## 2                                 41                                                                                   ##STR107##            0                                                                                 ##STR108## 3                                 42                                                                                   ##STR109##            0                                                                                 ##STR110## 3                                 43                                                                                   ##STR111##            0                                                                                 ##STR112## 3                                 44                                                                                   ##STR113##            0                                                                                 ##STR114## 3                                 45                                                                                   ##STR115##            1                                                                                 ##STR116## 3                                 46                                                                                   ##STR117##            0                                                                                 ##STR118## 3                                 47                                                                                   ##STR119##            0                                                                                 ##STR120## 3                                 48    Br                     5                                                                                 ##STR121## 3                                 49                                                                                   ##STR122##            0  SCH.sub.3   2                                 50                                                                                   ##STR123##            1  SCH.sub.3   2                                 51                                                                                   ##STR124##            2  SCH.sub.3   2                                 52                                                                                   ##STR125##            3  SCH.sub.3   2                                 53                                                                                   ##STR126##            0  SCH.sub.3   2                                 54                                                                                   ##STR127##            0  SCH.sub.3   2                                 55                                                                                   ##STR128##            0  SCH.sub.3   2                                 56                                                                                   ##STR129##            0  SCH.sub.3   2                                 57                                                                                   ##STR130##            0  SCH.sub.3   3                                 58                                                                                   ##STR131##            1  SCH.sub.3   3                                 59                                                                                   ##STR132##            2  SCH.sub.3   3                                 60                                                                                   ##STR133##            3  SCH.sub.3   3                                 61                                                                                   ##STR134##            0  SCH.sub.3   3                                 62                                                                                   ##STR135##            0  SCH.sub.3   3                                 63                                                                                   ##STR136##            0  SCH.sub.3   3                                 64                                                                                   ##STR137##            0  SCH.sub.3   3                                 65                                                                                   ##STR138##            0  SCH.sub.3   2                                 66                                                                                   ##STR139##            0  SCH.sub.3   2                                 67                                                                                   ##STR140##            0  SCH.sub.3   2                                 68                                                                                   ##STR141##            0  SCH.sub.3   2                                 69                                                                                   ##STR142##            1  SCH.sub.3   2                                 70                                                                                   ##STR143##            0  SCH.sub.3   2                                 71                                                                                   ##STR144##            0  SCH.sub.3   2                                 72    Br                     5  SCH.sub.3   2                                 73                                                                                   ##STR145##            0  SCH.sub.3   3                                 74                                                                                   ##STR146##            0  SCH.sub.3   3                                 75                                                                                   ##STR147##            0  SCH.sub.3   3                                 76                                                                                   ##STR148##            0  SCH.sub.3   3                                 77                                                                                   ##STR149##            1  SCH.sub.3   3                                 78                                                                                   ##STR150##            0  SCH.sub.3   3                                 79                                                                                   ##STR151##            0  SCH.sub.3   3                                 80    Br                     5  SCH.sub.3   3                                 81                                                                                   ##STR152##            0                                                                                 ##STR153## 3                                 82                                                                                   ##STR154##            1                                                                                 ##STR155## 3                                 83                                                                                   ##STR156##            2                                                                                 ##STR157## 3                                 84                                                                                   ##STR158##            3                                                                                 ##STR159## 3                                 85                 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                                                                   ##STR854##            0                                                                                 ##STR855## 3                                 470   Br                     5                                                                                 ##STR856## 3                                 471                                                                                  ##STR857##            0                                                                                 ##STR858## 3                                 472                                                                                  ##STR859##            1                                                                                 ##STR860## 3                                 473                                                                                  ##STR861##            2                                                     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                                                                   ##STR905##            0                                                                                 ##STR906## 1                                 496                                                                                  ##STR907##            0                                                                                 ##STR908## 1                                 497                                                                                  ##STR909##            0                                                                                 ##STR910## 1                                 498                                                                                  ##STR911##            1                                                                                 ##STR912## 1                                 499                                                                                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                     508                                                                                  ##STR931##            0                                                                                 ##STR932## 2                                 509                                                                                  ##STR933##            0                                                                                 ##STR934## 2                                 510                                                                                  ##STR935##            0                                                                                 ##STR936## 2                                 511                                                                                  ##STR937##            0                                                                                 ##STR938## 2                                 512                                                                                  ##STR939##            0                                                                                 ##STR940## 2                                 513                                                                                  ##STR941##            0                                                                                 ##STR942## 2                                 514                                                                                  ##STR943##            1                                                                                 ##STR944## 2                                 515                                                                                  ##STR945##            0                                                                                 ##STR946## 2                                 516                                                                                  ##STR947##            0                                                                                 ##STR948## 2                                 517   Br                     5                                                                                 ##STR949## 2                                 518   H                      0                                                                                 ##STR950## 2                                 519                                                                                  ##STR951##            0                                                                                 ##STR952## 2                                 520                                                                                  ##STR953##            1                                                                                 ##STR954## 2                                 521                                                                                  ##STR955##            2                                                                                 ##STR956## 2                                 522                                                                                  ##STR957##            3                                                                                 ##STR958## 2                                 523                                                                                  ##STR959##            0                                                                                 ##STR960## 2                                 524                                                                                  ##STR961##            0                                                                                 ##STR962## 2                                 525                                                                                  ##STR963##            0                                                     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        530                                                                                  ##STR973##            0                                                                                 ##STR974## 2                                 531                                                                                  ##STR975##            0                                                                                 ##STR976## 2                                 532                                                                                  ##STR977##            1                                                                                 ##STR978## 2                                 533                                                                                  ##STR979##            0                                                                                 ##STR980## 2                                 534                                                                                  ##STR981##            0                                                                                 ##STR982## 2                                 535   Br                     5                                                                                 ##STR983## 2                                 536   H                      0                                                                                 ##STR984## 2                                 537                                                                                  ##STR985##            0                                                                                 ##STR986## 3                                 538                                                                                  ##STR987##            1                                                                                 ##STR988## 3                                 539                                                                                  ##STR989##            2                                                                                 ##STR990## 3                                 540                                                                                  ##STR991##            3                                                                                 ##STR992## 3                                 541                                                                                  ##STR993##            0                                                                                 ##STR994## 3                                 542                                                                                  ##STR995##            0                                                                                 ##STR996## 3                                 543                                                                                  ##STR997##            0                                                                                 ##STR998## 3                                 544                                                                                  ##STR999##            0                                                                                 ##STR1000##                                                                              3                                 545                                                                                  ##STR1001##           0                                                                                 ##STR1002##                                                                              3                                 546                                                                                  ##STR1003##           0                                                                                 ##STR1004##                                                                              3                                 547                                                                                  ##STR1005##           0                                                                                 ##STR1006##                                                                              3                                 548                                                                                  ##STR1007##           0                                                                                 ##STR1008##                                                                              3                                 549                                                                                  ##STR1009##           1                                                                                 ##STR1010##                                                                              3                                 550                                                                                  ##STR1011##           0                                                                                 ##STR1012##                                                                              3                                 551                                                                                  ##STR1013##           0                                                                                 ##STR1014##                                                                              3                                 552   Br                     5                                                                                 ##STR1015##                                                                              3                                 553                                                                                  ##STR1016##           0                                        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                                                                 3                                 557                                                                                  ##STR1024##           0                                                                                 ##STR1025##                                                                              3                                 558                                                                                  ##STR1026##           0                                                                                 ##STR1027##                                                                              3                                 559                                                                                  ##STR1028##           0                                                                                 ##STR1029##                                                                              3                                 560                                                                                  ##STR1030##           0                                                                                 ##STR1031##                                                                              3                                 561                                                                                  ##STR1032##           0                                                                                 ##STR1033##                                                                              3                                 562                                                                                  ##STR1034##           0                                                                                 ##STR1035##                                                                              3                                 563                                                                                  ##STR1036##           0                                                                                 ##STR1037##                                                                              3                                 564                                                                                  ##STR1038##           0                                                                                 ##STR1039##                                                                              3                                 565                                                                                  ##STR1040##           1                                                                                 ##STR1041##                                                                              3                                 566                                                                                  ##STR1042##           0                                                                                 ##STR1043##                                                                              3                                 567                                                                                  ##STR1044##           0                                                                                 ##STR1045##                                                                              3                                 568                                                                                  ##STR1046##           0                                                                                 ##STR1047##                                                                              1                                 569                                                                                  ##STR1048##           1                                                                                 ##STR1049##                                                                              1                                 570                                                                                  ##STR1050##           2                                                                                 ##STR1051##                                                                              1                                 571                                                                                  ##STR1052##           3                                                                                 ##STR1053##                                                                              1                                 572                                                                                  ##STR1054##           0                                                                                 ##STR1055##                                                                              1                                 573                                                                                  ##STR1056##           0                                                                                 ##STR1057##                                                                              1                                 574                                                                                  ##STR1058##           0                                                                                 ##STR1059##                                                                              1                                 575                                                                                  ##STR1060##           0                                                                                 ##STR1061##                                                                              1                                 576                                                                                  ##STR1062##           0                                                                                 ##STR1063##                                                                              1                                 577                                                                                  ##STR1064##           0                                                                                 ##STR1065##                                                                              1                                 578                                                                                  ##STR1066##           0                                                                                 ##STR1067##                                                                              1                                 579                                                                                  ##STR1068##           0                                                                                 ##STR1069##                                                                              1                                 580                                                                                  ##STR1070##           1                                                                                 ##STR1071##                                                                              1                                 581                                                                                  ##STR1072##           0                                                                                 ##STR1073##                                                                              1                                 582                                                                                  ##STR1074##           0                                                                                 ##STR1075##                                                                              1                                 583   Br                     5                                                                                 ##STR1076##                                                                              1                                  ##STR1077##                                                                  584                                                                                  ##STR1078##           0                                                                                 ##STR1079##                                                                              2                                 585                                                                                  ##STR1080##           1                                                                                 ##STR1081##                                                                              2                                 586                                                                                  ##STR1082##           2                                                                                 ##STR1083##                                                                              2                                 587                                                                                  ##STR1084##           3                                                                                 ##STR1085##                                                                              2                                 588                                                                                  ##STR1086##           0                                                                                 ##STR1087##                                                                              2                                 589                                                                                  ##STR1088##           0                                                                                 ##STR1089##                                                                              2                                 590                                                                                  ##STR1090##           0                                                                                 ##STR1091##                                                                              2                                 591                                                                                  ##STR1092##           0                                                                                 ##STR1093##                                                                              2                                 592                                                                                  ##STR1094##           0                                                                                 ##STR1095##                                                                              2                                 593                                                                                  ##STR1096##           0                                                                                 ##STR1097##                                                                              2                                 594                                                                                  ##STR1098##           0                                                                                 ##STR1099##                                                                              2                                 595                                                                                  ##STR1100##           0                                                                                 ##STR1101##                                                                              2                                 596                                                                                  ##STR1102##           1                                                                                 ##STR1103##                                                                              2                                 597                                                                                  ##STR1104##           0                                                                                 ##STR1105##                                                                              2                                 598                                                                                  ##STR1106##           0                                                                                 ##STR1107##                                                                              2                                 599   Br                     5                                                                                 ##STR1108##                                                                              2                                 600   H                      0                                                                                 ##STR1109##                                                                              2                                 601                                                                                  ##STR1110##           0                                                                                 ##STR1111##                                                                              2                                 602                                                                                  ##STR1112##           1                                                                                 ##STR1113##                                                                              2                                 603                                                                                  ##STR1114##           2                                                                                 ##STR1115##                                                                              2                                 604                                                                                  ##STR1116##           3                                                                                 ##STR1117##                                                                              2                                 605                                                                                  ##STR1118##           0                                                                                 ##STR1119##                                                                              2                                 606                                                                                  ##STR1120##           0                                                                                 ##STR1121##                                                                              2                                 607                                                                                  ##STR1122##           0                                                                                 ##STR1123##                                                                              2                                 608                                                                                  ##STR1124##           0                                                                                 ##STR1125##                                                                              2                                 609                                                                                  ##STR1126##           0                                                                                 ##STR1127##                                                                              2                                 610                                                                                  ##STR1128##           0                                                                                 ##STR1129##                                                                              2                                 611                                                                                  ##STR1130##           0                                                                                 ##STR1131##                                                                              2                                 612                                                                                  ##STR1132##           0                                                                                 ##STR1133##                                                                              2                                 613                                                                                  ##STR1134##           1                                                                                 ##STR1135##                                                                              2                                 614                                                                                  ##STR1136##           0                                                                                 ##STR1137##                                                                              2                                 615                                                                                  ##STR1138##           0                                                                                 ##STR1139##                                                                              2                                 616   Br                     5                                                                                 ##STR1140##                                                                              2                                 617                                                                                  ##STR1141##           0                                                                                 ##STR1142##                                                                              3                                 618                                                                                  ##STR1143##           1                                                                                 ##STR1144##                                                                              3                                 619                                                                                  ##STR1145##           2                                                                                 ##STR1146##                                                                              3                                 620                                                                                  ##STR1147##           3                                                                                 ##STR1148##                                                                              3                                 621                                                                                  ##STR1149##           0                                                                                 ##STR1150##                                                                              3                                 622                                                                                  ##STR1151##           0                                                                                 ##STR1152##                                                                              3                                 623                                                                                  ##STR1153##           0                                                                                 ##STR1154##                                                                              3                                 624                                                                                  ##STR1155##           0                                                                                 ##STR1156##                                                                              3                                 625                                                                                  ##STR1157##           0                                                                                 ##STR1158##                                                                              3                                 626                                                                                  ##STR1159##           0                                                                                 ##STR1160##                                                                              3                                 627                                                                                  ##STR1161##           0                                                                                 ##STR1162##                                                                              3                                 628                                                                                  ##STR1163##           0                                                                                 ##STR1164##                                                                              3                                 629                                                                                  ##STR1165##           1                                                                                 ##STR1166##                                                                              3                                 630                                                                                  ##STR1167##           0                                                                                 ##STR1168##                                                                              3                                 631                                                                                  ##STR1169##           0                                                                                 ##STR1170##                                                                              3                                 632   Br                     5                                                                                 ##STR1171##                                                                              3                                 633                                                                                  ##STR1172##           0                                                                                 ##STR1173##                                                                              3                                 634                                                                                  ##STR1174##           1                                                                                 ##STR1175##                                                                              3                                 635                                                                                  ##STR1176##           2                                                                                 ##STR1177##                                                                              3                                 636                                                                                  ##STR1178##           3                                                                                 ##STR1179##                                                                              3                                 637                                                                                  ##STR1180##           0                                                                                 ##STR1181##                                                                              3                                 638                                                                                  ##STR1182##           0                                                                                 ##STR1183##                                                                              3                                 639                                                                                  ##STR1184##           0                                                                                 ##STR1185##                                                                              3                                 640                                                                                  ##STR1186##           0                                                                                 ##STR1187##                                                                              3                                 641                                                                                  ##STR1188##           0                                                                                 ##STR1189##                                                                              3                                 642                                                                                  ##STR1190##           0                                                                                 ##STR1191##                                                                              3                                 643                                                                                  ##STR1192##           0                                                                                 ##STR1193##                                                                              3                                 644                                                                                  ##STR1194##           0                                                                                 ##STR1195##                                                                              3                                 645                                                                                  ##STR1196##           1                                                                                 ##STR1197##                                                                              3                                 646                                                                                  ##STR1198##           0                                                                                 ##STR1199##                                                                              3                                 647                                                                                  ##STR1200##           0                                                                                 ##STR1201##                                                                              3                                 648                                                                                  ##STR1202##           0                                                                                 ##STR1203##                                                                              1                                 649                                                                                  ##STR1204##           1                                                                                 ##STR1205##                                                                              1                                 650                                                                                  ##STR1206##           2                                                                                 ##STR1207##                                                                              1                                 651                                                                                  ##STR1208##           3                                                                                 ##STR1209##                                                                              1                                 652                                                                                  ##STR1210##           0                                                                                 ##STR1211##                                                                              1                                 653                                                                                  ##STR1212##           0                                                                                 ##STR1213##                                                                              1                                 654                                                                                  ##STR1214##           0                                                                                 ##STR1215##                                                                              1                                 655                                                                                  ##STR1216##           0                                                                                 ##STR1217##                                                                              1                                 656                                                                                  ##STR1218##           0                                                                                 ##STR1219##                                                                              1                                 657                                                                                  ##STR1220##           0                                                                                 ##STR1221##                                                                              1                                 658                                                                                  ##STR1222##           0                                                                                 ##STR1223##                                                                              1                                 659                                                                                  ##STR1224##           0                                                                                 ##STR1225##                                                                              1                                 660                                                                                  ##STR1226##           1                                                                                 ##STR1227##                                                                              1                                 661                                                                                  ##STR1228##           0                                                                                 ##STR1229##                                                                              1                                 662                                                                                  ##STR1230##           0                                                                                 ##STR1231##                                                                              1                                 663   Br                     5                                                                                 ##STR1232##                                                                              1                                  ##STR1233##                                                                  664                                                                                  ##STR1234##           0                                                                                 ##STR1235##                                                                              2                                 665                                                                                  ##STR1236##           3                                                                                 ##STR1237##                                                                              2                                 666                                                                                  ##STR1238##           0                                                                                 ##STR1239##                                                                              2                                 667                                                                                  ##STR1240##           0                                                                                 ##STR1241##                                                                              2                                 668                                                                                  ##STR1242##           0                                                                                 ##STR1243##                                                                              2                                 669                                                                                  ##STR1244##           0                                                                                 ##STR1245##                                                                              2                                 670                                                                                  ##STR1246##           0                                                                                 ##STR1247##                                                                              2                                 671   H                      0                                                                                 ##STR1248##                                                                              2                                 672                                                                                  ##STR1249##           0                                                                                 ##STR1250##                                                                              2                                 __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Compd. No.                                                                          R.sub.1         m R.sub.2            n                                  __________________________________________________________________________     ##STR1251##                                                                  1001                                                                                 ##STR1252##    1                                                                                ##STR1253##       0                                  1002                                                                                 ##STR1254##    1                                                                                ##STR1255##       1                                  1003                                                                                 ##STR1256##    1                                                                                ##STR1257##       2                                  1004                                                                                 ##STR1258##    1                                                                                ##STR1259##       3                                  1005                                                                                 ##STR1260##    1                                                                                ##STR1261##       0                                  1006                                                                                 ##STR1262##    1                                                                                ##STR1263##       1                                  1007                                                                                 ##STR1264##    1                                                                                ##STR1265##       2                                  1008                                                                                 ##STR1266##    1                                                                                ##STR1267##       3                                  1009                                                                                 ##STR1268##    1                                                                                ##STR1269##       0                                  1010                                                                                 ##STR1270##    1                                                                                ##STR1271##       1                                  1011                                                                                 ##STR1272##    1                                                                                ##STR1273##       2                                  1012                                                                                 ##STR1274##    1                                                                                ##STR1275##       3                                  1013                                                                                 ##STR1276##    1                                                                                ##STR1277##       0                                  1014                                                                                 ##STR1278##    1                                                                                ##STR1279##       1                                  1015                                                                                 ##STR1280##    1                                                                                ##STR1281##       2                                  1016                                                                                 ##STR1282##    1                                                                                ##STR1283##       3                                  1017                                                                                 ##STR1284##    1                                                                                ##STR1285##       0                                  1018                                                                                 ##STR1286##    1                                                                                ##STR1287##       1                                  1019                                                                                 ##STR1288##    1                                                                                ##STR1289##       2                                  1020                                                                                 ##STR1290##    1                                                                                ##STR1291##       3                                  1021                                                                                 ##STR1292##    1                                                                                ##STR1293##       0                                  1022                                                                                 ##STR1294##    1                                                                                ##STR1295##       0                                  1023                                                                                 ##STR1296##    1                                                                                ##STR1297##       0                                  1024                                                                                 ##STR1298##    1                                                                                ##STR1299##       0                                  1025                                                                                 ##STR1300##    1                                                                                ##STR1301##       1                                  1026                                                                                 ##STR1302##    1                                                                                ##STR1303##       2                                  1027                                                                                 ##STR1304##    1                                                                                ##STR1305##       3                                  1028                                                                                 ##STR1306##    1                                                                                ##STR1307##       0                                  1029                                                                                 ##STR1308##    1                                                                                ##STR1309##       1                                  1030                                                                                 ##STR1310##    1                                                                                ##STR1311##       2                                  1031                                                                                 ##STR1312##    1                                                                                ##STR1313##       3                                  1032                                                                                 ##STR1314##    1                                                                                ##STR1315##       0                                  1033                                                                                 ##STR1316##    1                                                                                ##STR1317##       1                                  1034                                                                                 ##STR1318##    1                                                                                ##STR1319##       2                                  1035                                                                                 ##STR1320##    1                                                                                ##STR1321##       3                                  1036                                                                                 ##STR1322##    1                                                                                ##STR1323##       0                                  1037                                                                                 ##STR1324##    1                                                                                ##STR1325##       1                                  1038                                                                                 ##STR1326##    1                                                                                ##STR1327##       2                                  1039                                                                                 ##STR1328##    1                                                                                ##STR1329##       3                                  1040                                                                                 ##STR1330##    1                                                                                ##STR1331##       0                                  1041                                                                                 ##STR1332##    1                                                                                ##STR1333##       0                                  1042                                                                                 ##STR1334##    1                                                                                ##STR1335##       0                                  1043                                                                                 ##STR1336##    1                                                                                ##STR1337##       0                                  1044                                                                                 ##STR1338##    1                                                                                ##STR1339##       1                                  1045                                                                                 ##STR1340##    1                                                                                ##STR1341##       2                                  1046                                                                                 ##STR1342##    1                                                                                ##STR1343##       0                                  1047                                                                                 ##STR1344##    1                                                                                ##STR1345##       0                                  1048                                                                                 ##STR1346##    1                                                                                ##STR1347##       0                                  1049                                                                                 ##STR1348##    1                                                                                ##STR1349##       0                                  1050                                                                                 ##STR1350##    1                                                                                ##STR1351##       0                                  1051                                                                                 ##STR1352##    1                                                                                ##STR1353##       3                                  1052                                                                                 ##STR1354##    1                                                                                ##STR1355##       0                                  1053                                                                                 ##STR1356##    1                                                                                ##STR1357##       0                                  1054                                                                                 ##STR1358##    1                                                                                ##STR1359##       0                                  1055                                                                                 ##STR1360##    1                                                                                ##STR1361##       0                                  1056                                                                                 ##STR1362##    2                                                                                ##STR1363##       0                                  1057                                                                                 ##STR1364##    2                                                                                ##STR1365##       1                                  1058                                                                                 ##STR1366##    2                                                                                ##STR1367##       2                                  1059                                                                                 ##STR1368##    2                                                                                ##STR1369##       3                                  1060                                                                                 ##STR1370##    2                                                                                ##STR1371##       0                                  1061                                                                                 ##STR1372##    2                                                                                ##STR1373##       1                                  1062                                                                                 ##STR1374##    2                                                                                ##STR1375##       2                                  1063                                                                                 ##STR1376##    2                                                                                ##STR1377##       3                                  1064                                                                                 ##STR1378##    2                                                                                ##STR1379##       0                                  1065                                                                                 ##STR1380##    2                                                                                ##STR1381##       1                                  1066                                                                                 ##STR1382##    2                                                                                ##STR1383##       2                                  1067                                                                                 ##STR1384##    2                                                                                ##STR1385##       3                                  1068                                                                                 ##STR1386##    2                                                                                ##STR1387##       0                                  1069                                                                                 ##STR1388##    2                                                                                ##STR1389##       1                                  1070                                                                                 ##STR1390##    2                                                                                ##STR1391##       2                                  1071                                                                                 ##STR1392##    2                                                                                ##STR1393##       3                                  1072                                                                                 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       1984                                                                                 ##STR3164##    2                                                                                ##STR3165##       0                                  1985                                                                                 ##STR3166##    2                                                                                ##STR3167##       3                                  1986                                                                                 ##STR3168##    2                                                                                ##STR3169##       0                                  1987                                                                                 ##STR3170##    2                                                                                ##STR3171##       0                                  1988                                                                                 ##STR3172##    2                                                                                ##STR3173##       0                                  1989                                                                                 ##STR3174##    2                                                                                ##STR3175##       3                                  1990                                                                                 ##STR3176##    2                                                                                ##STR3177##       0                                  1991                                                                                 ##STR3178##    2                                                                                ##STR3179##       0                                  1992                                                                                 ##STR3180##    2                                                                                ##STR3181##       0                                  1993                                                                                 ##STR3182##    2                                                                                ##STR3183##       3                                  1994                                                                                 ##STR3184##    2                                                                                ##STR3185##       0                                  1995                                                                                 ##STR3186##    2                                                                                ##STR3187##       0                                  1996                                                                                 ##STR3188##    2                                                                                ##STR3189##       0                                  1997                                                                                 ##STR3190##    2                                                                                ##STR3191##       3                                  1998                                                                                 ##STR3192##    2                                                                                ##STR3193##       0                                  1999                                                                                 ##STR3194##    2                                                                                ##STR3195##       0                                  __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    Compd. No.                                                                          R.sub.1        m R.sub.2        n                                       __________________________________________________________________________     ##STR3196##                                                                  2001                                                                                 ##STR3197##   0                                                                                ##STR3198##   0                                       2002                                                                                 ##STR3199##   0                                                                                ##STR3200##   1                                       2003                                                                                 ##STR3201##   0                                                                                ##STR3202##   2                                       2004                                                                                 ##STR3203##   0                                                                                ##STR3204##   3                                       2005                                                                                 ##STR3205##   0                                                                                ##STR3206##   0                                       2006                                                                                 ##STR3207##   0                                                                                ##STR3208##   0                                       2007                                                                                 ##STR3209##   0                                                                                ##STR3210##   0                                       2008                                                                                 ##STR3211##   0                                                                                ##STR3212##   0                                       2009                                                                                 ##STR3213##   0                                                                                ##STR3214##   0                                       2010                                                                                 ##STR3215##   0                                                                                ##STR3216##   0                                       2011                                                                                 ##STR3217##   0                                                                                ##STR3218##   0                                       2012                                                                                 ##STR3219##   0                                                                                ##STR3220##   0                                       2013                                                                                 ##STR3221##   0                                                                                ##STR3222##   0                                       2014                                                                                 ##STR3223##   0                                                                                ##STR3224##   0                                       2015                                                                                 ##STR3225##   0                                                                                ##STR3226##   0                                       2016                                                                                 ##STR3227##   1                                                                                ##STR3228##   0                                       2017                                                                                 ##STR3229##   1                                                                                ##STR3230##   1                                       2018                                                                                 ##STR3231##   1                                                                                ##STR3232##   2                                       2019                                                                                 ##STR3233##   1                                                                                ##STR3234##   3                                       2020                                                                                 ##STR3235##   1                                                                                ##STR3236##   0                                       2021                                                                                 ##STR3237##   1                                                                                ##STR3238##   0                                       2022                                                                                 ##STR3239##   1                                                                                ##STR3240##   0                                       2023                                                                                 ##STR3241##   1                                                                                ##STR3242##   0                                       2024                                                                                 ##STR3243##   1                                                                                ##STR3244##   0                                       2025                                                                                 ##STR3245##   1                                                                                ##STR3246##   0                                       2026                                                                                 ##STR3247##   1                                                                                ##STR3248##   0                                       2027                                                                                 ##STR3249##   1                                                                                ##STR3250##   0                                       2028                                                                                 ##STR3251##   1                                                                                ##STR3252##   0                                       2029                                                                                 ##STR3253##   1                                                                                ##STR3254##   0                                       2030                                                                                 ##STR3255##   1                                                                                ##STR3256##   0                                       2031                                                                                 ##STR3257##   2                                                                                ##STR3258##   0                                       2032                                                                                 ##STR3259##   2                                                                                ##STR3260##   1                                       2033                                                                                 ##STR3261##   2                                                                                ##STR3262##   2                                       2034                                                                                 ##STR3263##   2                                                                                ##STR3264##   3                                       2035                                                                                 ##STR3265##   2                                                                                ##STR3266##   0                                       2036                                                                                 ##STR3267##   2                                                                                ##STR3268##   0                                       2037                                                                                 ##STR3269##   2                                                                                ##STR3270##   0                                       2038                                                                                 ##STR3271##   2                                                                                ##STR3272##   0                                       2039                                                                                 ##STR3273##   2                                                                                ##STR3274##   0                                       2040                                                                                 ##STR3275##   2                                                                                ##STR3276##   0                                       2041                                                                                 ##STR3277##   2                                                                                ##STR3278##   0                                       2042                                                                                 ##STR3279##   2                                                                                ##STR3280##   0                                       2043                                                                                 ##STR3281##   2                                                                                ##STR3282##   0                                       2044                                                                                 ##STR3283##   2                                                                                ##STR3284##   0                                       2045                                                                                 ##STR3285##   2                                                                                ##STR3286##   0                                       2046                                                                                 ##STR3287##   3                                                                                ##STR3288##   0                                       2047                                                                                 ##STR3289##   3                                                                                ##STR3290##   1                                       2048                                                                                 ##STR3291##   3                                                                                ##STR3292##   2                                       2049                                                                                 ##STR3293##   3                                                                                ##STR3294##   3                                       2050                                                                                 ##STR3295##   3                                                                                ##STR3296##   0                                       2051                                                                                 ##STR3297##   3                                                                                ##STR3298##   0                                       2052                                                                                 ##STR3299##   3                                                                                ##STR3300##   0                                       2053                                                                                 ##STR3301##   3                                                                                ##STR3302##   0                                       2054                                                                                 ##STR3303##   3                                                                                ##STR3304##   0                                       2055                                                                                 ##STR3305##   3                                                                                ##STR3306##   0                                       2056                                                                                 ##STR3307##   3                                                                                ##STR3308##   0                                       2057                                                                                 ##STR3309##   3                                                                                ##STR3310##   0                                       2058                                                                                 ##STR3311##   3                                                                                ##STR3312##   0                                       2059                                                                                 ##STR3313##   3                                                                                ##STR3314##   0                                       2060                                                                                 ##STR3315##   3                                                                                ##STR3316##   0                                       2061                                                                                 ##STR3317##   0                                                                                ##STR3318##   0                                       2062                                                                                 ##STR3319##   0                                                                                ##STR3320##   1                                       2063                                                                                 ##STR3321##   0                                                                                ##STR3322##   2                                       2064                                                                                 ##STR3323##   0                                                                                ##STR3324##   3                                       2065                                                                                 ##STR3325##   0                                                                                ##STR3326##   0                                       2066                                                                                 ##STR3327##   0                                                                                ##STR3328##   0                                       2067                                                                                 ##STR3329##   0                                                                                ##STR3330##   0                                       2068                                                                                 ##STR3331##   0                                                                                ##STR3332##   0                                       2069                                                                                 ##STR3333##   0                                                                                ##STR3334##   0                                       2070                                                                                 ##STR3335##   0                                                                                ##STR3336##   0                                       2071                                                                                 ##STR3337##   0                                                                                ##STR3338##   0                                       2072                                                                                 ##STR3339##   0                                                                                ##STR3340##   0                                       2073                                                                                 ##STR3341##   0                                                                                ##STR3342##   0                                       2074                                                                                 ##STR3343##   0                                                                                ##STR3344##   0                                       2075                                                                                 ##STR3345##   0                                                                                ##STR3346##   0                                       2076                                                                                 ##STR3347##   0                                                                                ##STR3348##   0                                       2077                                                                                 ##STR3349##   0                                                                                ##STR3350##   1                                       2078                                                                                 ##STR3351##   0                                                                                ##STR3352##   2                                       2079                                                                                 ##STR3353##   0                                                                                ##STR3354##   3                                       2080                                                                                 ##STR3355##   0                                                                                ##STR3356##   0                                       2081                                                                                 ##STR3357##   0                                                                                ##STR3358##   0                                       2082                                                                                 ##STR3359##   0                                                                                ##STR3360##   0                                       2083                                                                                 ##STR3361##   0                                                                                ##STR3362##   0                                       2084                                                                                 ##STR3363##   0                                                                                ##STR3364##   0                                       2085                                                                                 ##STR3365##   0                                                                                ##STR3366##   0                                       2086                                                                                 ##STR3367##   0                                                                                ##STR3368##   0                                       2087                                                                                 ##STR3369##   0                                                                                ##STR3370##   0                                       2088                                                                                 ##STR3371##   0                                                                                ##STR3372##   0                                       2089                                                                                 ##STR3373##   0                                                                                ##STR3374##   0                                       2090                                                                                 ##STR3375##   0                                                                                ##STR3376##   0                                       2091                                                                                 ##STR3377##   0                                                                                ##STR3378##   0                                       2092                                                                                 ##STR3379##   0                                                                                ##STR3380##   1                                       2093                                                                                 ##STR3381##   0                                                                                ##STR3382##   2                                       2094                                                                                 ##STR3383##   0                                                                                ##STR3384##   3                                       2095                                                                                 ##STR3385##   0                                                                                ##STR3386##   0                                       2096                                                                                 ##STR3387##   0                                                                                ##STR3388##   0                                       2097                                                                                 ##STR3389##   0                                                                                ##STR3390##   0                                       2098                                                                                 ##STR3391##   0                                                                                ##STR3392##   0                                       2099                                                                                 ##STR3393##   0                                                                                ##STR3394##   0                                       2100                                                                                 ##STR3395##   0                                                                                ##STR3396##   0                                       2101                                                                                 ##STR3397##   0                                                                                ##STR3398##   0                                       2102                                                                                 ##STR3399##   0                                                                                ##STR3400##   0                                       2103                                                                                 ##STR3401##   0                                                                                ##STR3402##   0                                       2104                                                                                 ##STR3403##   0                                                                                ##STR3404##   0                                       2105                                                                                 ##STR3405##   0                                                                                ##STR3406##   0                                        ##STR3407##                                                                  2106                                                                                 ##STR3408##   0                                                                                ##STR3409##   0                                       2107                                                                                 ##STR3410##   0                                                                                ##STR3411##   0                                       2108                                                                                 ##STR3412##   0                                                                                ##STR3413##   0                                       2109                                                                                 ##STR3414##   0                                                                                ##STR3415##   0                                       2110                                                                                 ##STR3416##   0                                                                                ##STR3417##   0                                       2111                                                                                 ##STR3418##   0                                                                                ##STR3419##   0                                       2112                                                                                 ##STR3420##   0                                                                                ##STR3421##   0                                       2113                                                                                 ##STR3422##   0                                                                                ##STR3423##   0                                       2114                                                                                 ##STR3424##   3                                                                                ##STR3425##   0                                       2115                                                                                 ##STR3426##   3                                                                                ##STR3427##   0                                       2116                                                                                 ##STR3428##   3                                                                                ##STR3429##   0                                       2117                                                                                 ##STR3430##   3                                                                                ##STR3431##   0                                       2118                                                                                 ##STR3432##   3                                                                                ##STR3433##   0                                       2119                                                                                 ##STR3434##   3                                                                                ##STR3435##   0                                       2120                                                                                 ##STR3436##   3                                                                                ##STR3437##   0                                       2121                                                                                 ##STR3438##   3                                                                                ##STR3439##   0                                        ##STR3440##                                                                  2122                                                                                 ##STR3441##   0                                                                                ##STR3442##   0                                       2123                                                                                 ##STR3443##   0                                                                                ##STR3444##   0                                       2124                                                                                 ##STR3445##   0                                                                                ##STR3446##   0                                       2125                                                                                 ##STR3447##   0                                                                                ##STR3448##   0                                       2126                                                                                 ##STR3449##   0                                                                                ##STR3450##   0                                       2127                                                                                 ##STR3451##   0                                                                                ##STR3452##   0                                       2128                                                                                 ##STR3453##   0                                                                                ##STR3454##   0                                       2129                                                                                 ##STR3455##   0                                                                                ##STR3456##   0                                       2130                                                                                 ##STR3457##   3                                                                                ##STR3458##   0                                       2131                                                                                 ##STR3459##   3                                                                                ##STR3460##   0                                       2132                                                                                 ##STR3461##   3                                                                                ##STR3462##   0                                       2133                                                                                 ##STR3463##   3                                                                                ##STR3464##   0                                       2134                                                                                 ##STR3465##   3                                                                                ##STR3466##   0                                       2135                                                                                 ##STR3467##   3                                                                                ##STR3468##   0                                       2136                                                                                 ##STR3469##   3                                                                                ##STR3470##   0                                       2137                                                                                 ##STR3471##   3                                                                                ##STR3472##   0                                        ##STR3473##                                                                  2138                                                                                 ##STR3474##   0                                                                                ##STR3475##   0                                       2139                                                                                 ##STR3476##   0                                                                                ##STR3477##   0                                       2140                                                                                 ##STR3478##   0                                                                                ##STR3479##   0                                       2141                                                                                 ##STR3480##   0                                                                                ##STR3481##   0                                       2142                                                                                 ##STR3482##   0                                                                                ##STR3483##   0                                       2143                                                                                 ##STR3484##   0                                                                                ##STR3485##   0                                       2144                                                                                 ##STR3486##   0                                                                                ##STR3487##   0                                       2145                                                                                 ##STR3488##   0                                                                                ##STR3489##   0                                       2146                                                                                 ##STR3490##   3                                                                                ##STR3491##   0                                       2147                                                                                 ##STR3492##   3                                                                                ##STR3493##   0                                       2148                                                                                 ##STR3494##   3                                                                                ##STR3495##   0                                       2149                                                                                 ##STR3496##   3                                                                                ##STR3497##   0                                       2150                                                                                 ##STR3498##   3                                                                                ##STR3499##   0                                       2151                                                                                 ##STR3500##   3                                                                                ##STR3501##   0                                       2152                                                                                 ##STR3502##   3                                                                                ##STR3503##   0                                       2153                                                                                 ##STR3504##   3                                                                                ##STR3505##   0                                        ##STR3506##                                                                  2154                                                                                 ##STR3507##   0                                                                                ##STR3508##   0                                       2155                                                                                 ##STR3509##   0                                                                                ##STR3510##   0                                       2156                                                                                 ##STR3511##   0                                                                                ##STR3512##   0                                       2157                                                                                 ##STR3513##   0                                                                                ##STR3514##   0                                       2158                                                                                 ##STR3515##   0                                                                                ##STR3516##   0                                       2159                                                                                 ##STR3517##   0                                                                                ##STR3518##   0                                       2160                                                                                 ##STR3519##   0                                                                                ##STR3520##   0                                       2161                                                                                 ##STR3521##   0                                                                                ##STR3522##   0                                       2162                                                                                 ##STR3523##   3                                                                                ##STR3524##   0                                       2163                                                                                 ##STR3525##   3                                                                                ##STR3526##   0                                       2164                                                                                 ##STR3527##   3                                                                                ##STR3528##   0                                       2165                                                                                 ##STR3529##   3                                                                                ##STR3530##   0                                       2166                                                                                 ##STR3531##   3                                                                                ##STR3532##   0                                       2167                                                                                 ##STR3533##   3                                                                                ##STR3534##   0                                       2168                                                                                 ##STR3535##   3                                                                                ##STR3536##   0                                       2169                                                                                 ##STR3537##   3                                                                                ##STR3538##   0                                       __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                        Compd. No.                                                                    ______________________________________                                        3001                                                                                    ##STR3539##                                                         3002                                                                                    ##STR3540##                                                         3003                                                                                    ##STR3541##                                                         3004                                                                                    ##STR3542##                                                         3005                                                                                    ##STR3543##                                                         3006                                                                                    ##STR3544##                                                         3007                                                                                    ##STR3545##                                                         3008                                                                                    ##STR3546##                                                         3009                                                                                    ##STR3547##                                                         3010                                                                                    ##STR3548##                                                         3011                                                                                    ##STR3549##                                                         3012                                                                                    ##STR3550##                                                         3013                                                                                    ##STR3551##                                                         3014                                                                                    ##STR3552##                                                         3015                                                                                    ##STR3553##                                                         3016                                                                                    ##STR3554##                                                         3017                                                                                    ##STR3555##                                                         3018                                                                                    ##STR3556##                                                         3019                                                                                    ##STR3557##                                                         3020                                                                                    ##STR3558##                                                         3021                                                                                    ##STR3559##                                                         3022                                                                                    ##STR3560##                                                         3023                                                                                    ##STR3561##                                                         3024                                                                                    ##STR3562##                                                         3025                                                                                    ##STR3563##                                                         3026                                                                                    ##STR3564##                                                         3027                                                                                    ##STR3565##                                                         3028                                                                                    ##STR3566##                                                         3029                                                                                    ##STR3567##                                                         3030                                                                                    ##STR3568##                                                         3031                                                                                    ##STR3569##                                                         3032                                                                                    ##STR3570##                                                         3033                                                                                    ##STR3571##                                                         3034                                                                                    ##STR3572##                                                         3035                                                                                    ##STR3573##                                                         3036                                                                                    ##STR3574##                                                         3037                                                                                    ##STR3575##                                                         3038                                                                                    ##STR3576##                                                         3039                                                                                    ##STR3577##                                                         3040                                                                                    ##STR3578##                                                         3041                                                                                    ##STR3579##                                                         3042                                                                                    ##STR3580##                                                         3043                                                                                    ##STR3581##                                                         3044                                                                                    ##STR3582##                                                         3045                                                                                    ##STR3583##                                                         3046                                                                                    ##STR3584##                                                         3047                                                                                    ##STR3585##                                                         3048                                                                                    ##STR3586##                                                         ______________________________________                                    

NMR DATA OF EXAMPLES EXAMPLE 1

(Reaction1)

NMR(DMSO-d₆) δ: 9.64(s, 1H), 8.33(s, 1H), 7.65(s, 1H), 3.95(s, 1H)

EXAMPLE 1

(Reaction2)

NMR(DMSO-d₆) δ: 8.28(d, 1H), 8.17(s, 1H), 7.86(d, 1H), 7.67(d, 1H),7.56(d, 1H), 4.19(s, 3H), 3.88(s, 3H)

EXAMPLE 1

(Reaction3)

NMR(DMSO-d₆) δ: 8.30(d, 1H), 8.17(s, 1H), 7.85(d, 1H), 7.65(d, 1H),7.59(d, 1H), 4.20(s, 3H)

EXAMPLE 2

(Reaction2)

NMR(DMSO-d₆) δ: 9. 09(s, 2H), 8.85(bs, 0.5H), 8.74(bs, 0.5), 8.71(s,2H), 8.29(s, 1H), 8.07(s, 0.5H), 7.83-7.54(m, 3.5H), 4.20(s, 3H),3.63(q, 2H), 2.71(t, 2H)

EXAMPLE 2

(Reaction3)

NMR(DMSO-d₆) δ: 9.91(1H, s), 9.03(2H, bs), 8.70(1H, br), 8.62(2H, bs),8.20-7.90(1H, m), 7.70(1H, m), 7.65-7.4(1H, m), 7.09(1H, s), 7.05(2H,d), 6.91(1H, br), 6.68 (2H, d), 4.06(3H, s), 3.70(8H,m), 3.62(2H, m),2.69(2H, m), 2.49(2H, m), 1.83(2H, m)

EXAMPLE 3

NMR9.92(1H, s), 9.06(2H, bs), 8.73(1H, br), 8.66(2H, bs), 8.20-7.90(1H,m), 7.71(1H, m), 7.65-7.40(1H, m), 7.27(1H, s), 7.05(2H, d), 6.90(1H,br), 6.67(2H, d), 4.06(3H, s), 3.70(8H, m), 3.63(2H, m), 2.70(2H, m),2.50(2H, m), 2.27(2H, m), 1.83(2H, m),

EXAMPLE 4

NMR (DMSO-d₆) δ: 9.90(s, 1H), 8.94(bs, 2H), 8.59(bs, 2H), 8.49(bs, 1H),8.16(bs, 1H, 7.88(d, 1H)), 7.73(d, 1H), 7.52(bs, 1H), 7.36(d, 1H),7.13(s, 1H), 6.85(d, 2H), 4.11(s, 3H), 3.80(m, 8H), 3.67(q, 2H), 2.76(t,2H)

EXAMPLE 5

NMR (DMSO-d₆) δ: 10.24(s, 1H), 8.98(bs, 2H), 8.66(bs, 2H), 8.52(bs, 1H),7.96(s, 1H), 7.92(s, 1H), 7.74(d, 1H), 7.56-7.44(m, 5H), 7.40(d, 1H),7.16(bs, 1H), 4.12(s, 3H), 3.64(bs, 2H), 2.70(t, 2H)

EXAMPLE 6

NMR(DMSO-d₆) δ: 10.5(1H, s), 9.20(2H, bs), 8.85(2H, s), 8.80(1H, br),8.14(1H, br), 7.77(1H, m), 7.63-7.35(4H, m), 7.33(1H, s), 7.04(1H, s),4.08(3H, s), 4.07(2H, m), 2.74(2H, m)

EXAMPLE 7

(Reaction1)

NMR(DMSO-d₆) δ: 8.55(1H, br), 8.26(1H, s), 8.12(1H, br), 7.75(1H, d),7.63(1H, br), 7.55(1H, s), 3.60-3.30(2H, m), 2.37(2H, t), 2.22(6H, s),1.71(2H, q)

EXAMPLE 7

(Reaction2)

NMR(DMSO-d₆) δ: 10.4(1H, s), 8.65(1H, br), 8.1(1H, m), 7.80-7.50(2H, m),7.31(1H, s), 6.99(1H, s), 4.08(3H, s), 4.04(2H, m), 3.4(2H, m), 3.10(2H,m), 2.77(6H, s), 1.93(2H, m)

EXAMPLE 8

NMR(CDCl₃ +DMSO-d₆) δ: 9.39(1H, br), 8.40(1H, br), 8.20(1H, s), 8.09(1H,s), 7.50(2H, br), 7.20(1H, br), 6.86(1H,s), 5.52(2H, m), 3.99(3H, s),2.48(2H, t), 6H, s), 1.78(2H, q)

EXAMPLE 9

NMR(DMSO-d₆) δ: 9.80(1H, s), 8.06(1H, s), 7.74(2H, m), 7.25(2H, m),7.02(2H, d), 7.0 (1H, m), 6.66(2H, d), 3.86(3H, s), 3.38(8H, m),2.77(4H, m), 2.54(2H , m), 2.48(2H, m), 2.21(2H,m), 1.80(2H, m)

EXAMPLE 10

(Reaction2)

NMR(DMSO-d₆) δ: 10.15(1H, s), 8.15(1H, s), 8.14(1H, s), 7.83(2H, m),7.30(1H, s), 7.25(1H, s), 7.02(1H, s), 3.89(3H, s), 3.78(6H, s),3.65(3H, s)

EXAMPLE 11

(Reaction1)

NMR(CDCl₃ +DMSO-d₆) δ: 8.10(bs, 1H), 8.02(s, 1H), 7.68(m, 3H), 7.57(s,1H), 4.26(s, 3H), 34.6(q, 2H), 1.65(m, 2H), 1.25(s, 30H), 0.88(t, 3H)

EXAMPLE 11

(Reaction2)

NMR(DMSO-d₆) δ10.04(s, 1H), 8.35-8.29(m, 1H), 8.09(s, 0.5H), 7.86(s,0.5H), 7.80(d, 2H, J=8.8), 7.66-7.58(d, 1H), 7.53(d, 0.5H), 7.37(d,0.5H), 7.34(s, 1H), 7.05(s, 0.5H), 7.01(s, 0.5H), 6.77(d, 2H), 4.02(s,3H), 3.73(m, 8H), 3.21(m, 2H)

EXAMPLE 12

NMR(DMSO-d₆) δ: 10.08(s, 1H), 8.32(m, 1H), 8.09(s, 1H+0.5H), 7.88(s,0.5H), 7.66-7.58(d, 1H), 7.54(d, 0.5H), 7.36(d, 0.5H), 7.21(s, 1H),6.95(s, 1H), 4.00(s, 3H), 3.19(m, 2H), 1.46(m, 2H), 1.15(s, 30H),0.78(t, 3H)

EXAMPLE 13

(Reaction1)

NMR(CDCl₃) δ: 8.04(d, 2H), 7.46(d, 2H), 4.62(s, 2H), 3.92(s, 3H)

EXAMPLE 13

(Reaction2)

NMR(CDCl₃) δ: 8.00(d,J=7.8,2H), 7.41(d,J=8.6,2H), 3.92(s, 3H), 3.77(s,2H), 3.64(t,J=5.1,4H), 2.73(t,J=5.1,4H)

EXAMPLE 13

(Reaction4)

NMR(DMSO-d₆) δ: 7.99(d, 2H), 7.74(d, 2H), 4.42(bs, 2H), 3.99(bs, 4H),3.37(bs, 4H)

EXAMPLE 13

(Reaction6)

NMR(DMSO-d₆) δ: 10.44(s, 1H), 9.05(s, 2H), 8.64(s, 2H), 8.18(bs, 1H),8.01(bs, 1H), 7.75(s, 1H), 7.49(d, 2H), 7.46(d, 1H), 7.17(s, 1H),4.21(s, 3H), 3.83(s, 2H), 3.66(m, 6H), 2.89(t, 4H), 2.71(t, 2H)

EXAMPLE 14

(Reaction1)

NMR(DMSO-d₆) δ: 8.50(t, 0.5H), 8.42(t, 0.5H), 8.29(d, 1H), 8.24(s,0.5H), 8.00(s, 0.5H), 7.81-7.57(m, 2H), 7.57(s, 1H), 4.19(s, 3H),3.28(q, 2H), 1.54m, 2H), 1.35(m, 2H), 0.92(t, 3H)

EXAMPLE 14

(Reaction2)

NMR(DMSO-d₆, 80° C.) δ: 8.09(bs, 1H), 7.66(bd, 1H), 7.56-7.43(bm, 1H),7.20(s, 1H), 6.92(s, 1H), 4.07(s, 3H), 3.28(m, 2H), 1.52(m, 2H), 1.35(m,2H), 0.92(t, 3H)

EXAMPLE 15

NMR(DMSO-d₆, 80°) δ: 9.85(s, 1H), 8.11(m, 1H), 7.86(d, 2H), 7.65(d, 1H),7.55-7.38(m, 2H), 7.33(s, 1H), 7.08(s, 1H), 6.84(d, 2H), 4.09(s, 3H),3.78(m, 8H)3.29(q, 2H), 1.56(m, 2H), 1.38(m, 2H), 0.93(3H)

EXAMPLE 16

(Reaction1)

NMR(CDCl₃) δ: 7.77(dd, 1H), 7.52(dt, 1H), 7.39(d, 1H), 7.21(t, 1H),4.39(q, 2H), 3.54(t, 4H), 3.22(t, 4H), 1.40(t, 3H)

EXAMPLE 16

(Reaction2)

NMR(CDCl₃) δ: 8.17(dd, 1H), 7.63(t, 1H), 4.52(q, 6H), 3.78(t, 4H),1.47(t, 3H)

EXAMPLE 16

(Reaction3)

NMR(CDCl₃) δ: 7.85(dd, 1H), 7.56(m, 2H), 7.29(dt, 1H), 3.64(t, 4H),3.50(t, 4H)

EXAMPLE 16

(Reaction4)

NMR(DMSO-d₆) δ: 10.67(s, 1H), 8.94(bs, 2H), 8.58(bs, 2H), 8.48(bt, 1H),8.09(bs, 1H), 7.52(d, 1H), 7.47(d, 1H), 7.39(d, 1H), 7.37(s, 1H),7.23(t, 1H), 7.07(s, 1H), 3.69(m, 6H), 3.54(t, 4H), 2.74(s, 2H)

EXAMPLE 17

(Reaction1)

NMR(CDCl₃) δ: 7.37-7.22(m, 3H), 6.86(d, 1H), 3.87(s, 3H), 3.82(t, 4H),3.58(t, 4H)

EXAMPLE 17

(Reaction2)

NMR(CDCl₃) δ: 7.44(d, 1H), 7.35(s, 1H), 7.29(t, 1H), 6.88(d, 1H),3.91(s, 3H), 3.79(t, 4H), 3.66(t, 4H)

EXAMPLE 17

(Reaction3)

NMR(CDCl₃ +DMSO-d₆) δ: 7.48-7.29(m, 3H), 6.90(dd, 1H), 3.82-3.77(m, 4H),3.69-3.64(m, 4H)

EXAMPLE 17

(Reaction4)

NMR(DMSO-d₆) δ: 10.38(s, 1H), 9.02(bs, 2H), 8.73(t, 0.5H), 8.67(t,0.5H), 8.60(bs, 2H), 8.20(s, 0.5H), 7.96(s, 0.5H), 7.73(d, 0.5H),7.70(d, 0.5H), 7.63(d, 0.5H), 7.47(d, 0.5H), 7.45(s, 1H), 7.35(d, 1H),7.28(t, 1H), 7.23(s, 1H), 7.18(s, 0.5H), 7.13 (s, 0.5H), 6.96(d, 1H),4.11(s, 3H), 3.80(s, 8H), 3.63(m, 2H), 2.68(m, 2H)

EXAMPLE 18

(Reaction1)

NMR(CDCl₃) δ: 8.22(d, 2H), 6.98(d, 2H), 4.74(s, 2H), 3.83(s, 3H)

EXAMPLE 18

(Reaction4)

NMR(DMSO-d₆) δ: 6.83(2H, d), 6.69(2H, d), 4.67(2H, s), 3.75-3.60(11H, m)

EXAMPLE 18

(Reaction5)

NMR(DMSO-d₆) δ: 7.68(1H, br, D₂ O exchangeable), 6.82(2H, d), 6.71(2H,d), 4.55(2H, s), 3.67(8H, bs)

EXAMPLE 18

(Reaction6)

NMR(DMSO-d₆) δ: 10.2(1H, s), 9.03(2H, br), 8.80-8.63(1H, m), 8.61(2H,br), 8.19(0.6H, m), 7.96(0.4H, m), 7.28-7.76(3H, m), 7.06(1H, m),6.93(2H, d), 6.73(2H, d), 4.56(2H, s), 4.07(3H, s), 3.67(8H, m),3.63(2H, m), 2.69(2H, t)

EXAMPLE 19

(Reaction1)

NMR(CDCl₃) δ: 6.46(d, 2H), 6.05(t, 1H), 5.15(bs, 4H), 3.75(s, 3H)

EXAMPLE 19

(Reaction5)

NMR(DMSO-d₆) δ: 10.3(1H, s), 9.00(2H, bs), 8.72(0.42H, m), 8.64(0.58H,m), 8.59(2H, bs), 8.20(0.58H, s), 7.95(0.42H, d, J=2.2), 7.4-7.76(3H,m), 7.15(0.42H, d,J=2.2), 7.10(0.58H, d,J=2.2), 6.61(2H, s), 6.15(1H,s), 4.11(3H, s), 3.79(16H, bs), 3.63(2H, m), 2.68(2H, m)

EXAMPLE 20

(Reaction1)

NMR(CDCl₃) δ: 7.13(d, 2H), 6.65(d, 2H), 3.84(t, 2H), 3.68(s, 3H),3.56(t, 2H), 3.52(s, 2H)

EXAMPLE 20

(Reaction2)

NMR(CDCl₃) δ: 7.17(d, 2H), 6.65(d, 2H), 3.75-3.69(m, 4H), 3.69(s, 3H),3.65-3.59(m, 4H), 3.54(s, 2H)

EXAMPLE 20

(Reaction3)

NMR(CDCl₃) δ: 7.16(d, 2H), 6.65(d, 2H), 3.75-3.69(d, 4H), 3.65-3.59(m,4H), 3.55(s, 3H)

EXAMPLE 20

(Reaction4)

NMR(DMSD-d₆) δ: 10.12(s, 1H), 9.02(bs, 2H), 8.72(t, 0.5H), 8.64(t,0.5H), 8.61(bs, 2H), 8.18(s, 0.5H), 7.95(s, 0.5H), 7.72(d, 0.5H),7.70(d, 0.5H), 7.61(d, 0.5H), 7.46(d, 0.5H), 7.24(s, 1H), 7.17(d, 2H),6.96(s, 0.5H), 6.91(s, 0.5H), 6.70(d, 2H), 4.05(s, 3H), 3.71(s, 8H),3.62(m, 2H), 3.44(s, 2H), 2.68(m, 2H)

EXAMPLE 21

(Reaction1)

NMR(CDCl₃) δ: 7.84(d, 1H), 7.76(d, 1H), 7.68(dd, 1H), 4.02(s, 3H),3.97(s, 3H)

EXAMPLE 21

(Reaction2)

NMR(CDCl₃) δ: 7.55(dd, 1H), 7.45(d, 1H), 6.66(d, 1H), 4.22(bs, 2H),3.90(s, 3H), 3.86(s, 3H)

EXAMPLE 21

(Reaction3)

NMR(CDCl₃) δ: 7.64(dd, 1H), 7.56(d, 1H), 7.10(d, 1H), 3.92(s, 3H),3.90(s, 3H), 3.66(t, 4H), 3.37(t, 4H), 2.95(bs, 2H)

EXAMPLE 21

(Reaction4)

NMR(CDCl₃) δ: 7.96(d, 1H), 7.70(d, 1H), 7.69(s, 1H), 4.04(s, 3H),3.95(s, 3H), 3.87(t, 4H), 3.72(t, 4H)

EXAMPLE 21

(Reaction5)

NMR(CDCl₃) δ: 7.49(dd, 1H), 7.44(d, 1H), 7.01(d, 1H), 3.84(s, 3H),3.65(m, 8H)

EXAMPLE 21

(Reaction6)

NMR(DMSO-d₆) δ: 10.02(s, 1H), 8.92(bs, 2H), 8.53(bs, 2H), 8.46(bs, 1H),8.17(bs 0.5H), 7.96(bs, 0.5H), 7.72(d, 1H), 7.56(s, 1H), 7.55(d, 1H),7.36(s, 1H), 7.13(bs, 1H), 7.07(d, 1H), 4.10(s, 3H), 3.90(s, 3H),3.64(m, 10H), 2.74(t, 2H)

EXAMPLE 22

(Reaction5)

NMR(DMSO-d₆) δ: 9.92(s, 1H), 9.02(bs, 2H), 8.63(bm, 1H), 8.57(bs, 2H),8.18bs, 0.5H), 7.96(bs, 0.5H), 7.71(bd, 1H), 7.61(bs, 0.5H), 7.47(bs,0.5H), 7.26(s, 1H), 7.08(d, 2H), 6.91(bs, 1H), 6.66(d, 2H), 4.07(s, 3H),3.69(s, 8H), 3.65(m, 2H), 2.83(t, 2H), 2.69(t, 2H), 2.52(m, 2H)

EXAMPLE 23

(Reaction3)

NMR(DMSO-d₆) δ: 9.78(s, 1H), 8.85(bs, 2H), 8.36(1H+2H), 8.07(s, 1H+1H),7.86(d, 2H), 7.70(d, 1H), 7.53(d, 1H), 7.32(s, 1H), 7.11(s, 1H), 6.83(d,2H), 4.09(s, 3H), 3.82(m, 1H), 3.64(m, 2H), 2.74(t, 2H)

EXAMPLE 24

(Reaction2)

NMR(DMSO-d₆) δ: 10.67(s, 1H), 8.97(t, 1H), 8.28(s, 1H), 8.14(bs, 3H),8.00(d, 3H), 7.76(d, 1H), 7.70(s, 1H), 7.59-7.50(m, 3H), 7.37(s, 1H),4.12(s, 3H), 3.58(q, 2H), 3.03(q, 2H)

EXAMPLE 25

(Reaction3)

NMR(DMSO-d₆) δ: 10.34(s, 1H), 8.97(t, 1H), 8.27(s, 1H), 8.15(bs, 2H),7.99(d, 1H), 7.90(d, 2H), 7.76(d, 1H), 7.66(s, 1H), 7.35(s, 1H), 6.85(d,2H), 4.11(s, 3H), 3.80(m, 8H), 3.58(q, 2H), 3.02(q, 2H)

EXAMPLE 26

(Reaction2)

NMR(DMSO-d₆) δ: 10.33(s, 1H), 9.58(t, 1H), 8.94(s, 1H), 8.84(d, 1H),8.55(d, 1H), 8.27(s, 1H), 8.04(dd, 1H), 7.98(d, 1H), 7.91(d, 2H),7.76(d, 1H), 7.65(s, 1H), 7.33(s, 1H), 6.86(d, 2H), 4.70(d, 2H), 4.11(s,3H), 3.80(bs, 8H)

EXAMPLE 27

NMR(DMSO-d₆) δ: 10.15(s, 1H), 9.30(bs, 1H), 9.03(s, 1H), 8.89(d, 1H),8.54(d, 1H), 8.33(s, 0.5H), 8.25(bs, 0.5H), 8.11(dd, 1H), 7.87(d, 2H),7.77(d, 1H), 7.57(bm, 1H), 7.43(s, 1H), 7.15(s, 1H), 6.85(d, 2H),4.67(d, 2H), 4.37(s, 3H), 4.10(s, 3H), 3.79(m, 8H)

EXAMPLE 28

NMR(DMSO-d₆) δ: 9.48(s, 1H), 8.82(bs, 2H), 8.38(bs, 2H), 8.32(t, 1H),8.06s, 1H), 7.70(d, 1H), 7.50(d, 1H), 7.16(s, 1H), 6.92(s, 1H), 4.05(s,3H), 3.65(q, 2H), 3.61(t, 2H), 2.75(t, 2H), 2.28(t, 2H), 1.76(m, 2H),1.63(m, 2H), 1.47(m, 2H)

EXAMPLE 29

(Reaction1)

NMR(DMSO-d₆) δ: 10.1(3H, br), 7.20(2H), 6.82(2H, d), 3.73(8H, s)

EXAMPLE 29

(Reaction2)

NMR(DMSO-d₆): 10.08(s, 0.5H), 10.01(s, 0.5H), 8.40(s, 0.5H), 8.40(s,0.5H), 8.10(s, 0.5H), 8.31(s, 1H), 7.91-7.83(m, 1H), 7.75-7.58(m, 4H),6.76(d, 2H), 4.21(s, 3H), 3.73(s, 8H)

EXAMPLE 29

(Reaction3)

NMR(DMSO-d₆) δ: 10.32(s, 1H), 10.04(s, 0.5H), 9.97(s, 0.5H), 8.32(s,0.5H), 8.03(s, 0.5H), 7.81(d, 1H), 7.67-7.50(m, 3H), 7.60-7.20(bs, 5H),7.30(s, 1H), 6.99(s, 0.5H), 6.97(s, 0.5H), 6.75(d, 2H), 4.09(s, 3H),4.03(d, 2H), 3.73(s, 8H)

EXAMPLE 30

(Reaction4)

NMR(DMSO-d₆) δ: 10.32(s, 1H), 10.00(s, 0.5H), 9.94(s, 0.5H), 8.31(s,0.5H), 8.03(s, 0.5H), 7.82(d, 0.5H), 7.79(d, 0.5H), 7.68-7.53(m, 3H),7.50-7.17(bs, 4H), 7.30(s, 1H), 6.99(s, 0.5H), 6.97(s, 0.5H), 6.78(d,2H), 4.16(t, 4H), 4.09(s, 3H), 4.03(d, 2H), 3.59(t, 4H), 2.01(s, 6H)

EXAMPLE 31

(Reaction3)

NMR(DMSO-d₆) δ: 10.32(s, 1H), 8.55(t, 0.4H), 8.48(t, 0.6H), 8.15(s,0.6H), 7.93s, 0.4H), 7.74(d, 0.4H), 7.70(d, 0.6H), 7.62(s, 1H), 7.60(m,0.6H), 7.46(d, 0.4H), 7.43-7.20(bs, 4H), 7.10(d, 2H), 6.98(s, 0.4H),6.95(s, 0.6H), 6.79(d, 2H), 4.08(s, 3H), 4.03(d, 2H), 3.70(s, 8H),3.43(q, 2H), 2.75(t, 2H)

EXAMPLE 32

(Reaction1)

NMR(DMSO-d₆) δ; 7.07(d, 2H), 6.62(d, 2H), 3.73-3.56(m, 8H), 2.86(bs,2H), 2.76-2.72(m, 2H), 2.59-2.51(m, 2H), 1.82-1.74(m, 2H)

EXAMPLE 32

(Reaction2)

NMR(DMSO-d₆) δ: 8.52(t, 0.5H), 8.44(t, 0.5H), 8.30(s, 1H), 8.25(s,0.5H), 7.99(s, 0.5H), 7.79(d, 0.5H), 7.76-7.71(m, 1H), 7.58-7.54(m,0.5H), 7.07(d, 2H), 6.67(d, 2H), 4.19(s, 3H), 3.70(s, 8H), 3.32(q, 2H),2.53(t, 2H), 1.80(m, 2H)

EXAMPLE 32

(Reaction3)

NMR(DMSO-d₆) δ: 10.34(s, 1H), 8.47(t, 0.5H), 8.41(t, 0.5H), 8.17(s,0.5H), 7.94(s, 0.5H), 7.74-7.62(m, 2.5H), 7.48-7.29(m, 5.5H), 7.08(d,2H), 6.98(s, 0.5H), 6.95(s, 0.5H), 6.67(d, 2H), 4.08(s, 3H), 4.04(q,2H), 3.30(m, 2H), 1.79(m, 2H)

EXAMPLE 33

NMR(DMSO-d₆) δ: 10.13(s, 1H), 9.98-10.02(m, 1H), 8.33(s, 0.5H), 8.03(s,0.5H), 7.88(d, 2H), 7.81(d, 1H), 7.65(d, 2H), 7.52(d,. 1H), 7.43(s, 1H),7.13(s, 1H), 6.85(d, 2H), 6.76(d, 2H), 4.11(s, 3H), 3.80(s, 8H), 3.73(s,8H)

EXAMPLE 34

(Reaction1)

NMR(CDCl₃) δ: 9.83(s, 1H), 7.28(s, 1H), 7.12(s, 1H), 4.03(s, 3H)

EXAMPLE 34

(Reaction2)

NMR(CDCl₃) δ: 9.85(s, 1H), 7.91(s, 1H), 4.13(s, 3H)

EXAMPLE 34

(Reaction3)

NMR(DMSO-d₆) δ: 8.71(s, 1H), 8.31(s, 0.5H), 8.15(s, 0.5H), 7.93(d,0.5H), 7.60(d, 0.5H), 4.28(s, 3H)

EXAMPLE 34

(Reaction4)

NMR(DMSO-d₆) δ: 8.88(bs, 1H), 8.71(s, 1H), 8.32(s, 0.5H), 8.08(s, 0.5H),7.95-7.60(m, 2H), 4.28(s, 3H), 3.53(q, 2H), 2.81(t, 2H)

EXAMPLE 34

(Reaction5)

NMR(DMSO-d₆) δ: 9.04(bs, 2H), 8.83(t, 0.5H), 8.75(s, 1H), 8.73(s, 1H),8.63(bs, 2H), 8.34(s, 0.5H), 8.07(s, 0.5H), 7.87(d, 0.5H), 7.80(bs, 1H),7.57(d, 0.5H), 4.28(s, 3H), 3.63(q, 2H), 2.69(t, 2H)

EXAMPLE 34

(Reaction6)

NMR(DMSO-d₆) δ: 10.41(s, 1H), 9.03(bs, 2H), 8.74(bs, 1H), 8.60(bs, 2H),8.20(s, 1H), 7.94(d, 2H), 7.80(d, 1H), 7.68(s, 1H), 7.65(d, 1H), 6.82(d,2H), 4.20(s, 3H), 3.79(m, 8H), 3.64(m, 2H), 2.70(m, 2H)

EXAMPLE 35

NMR(DMSO-d₆) δ: 10.22(s, 1H), 9.01(bs, 2H), 8.74(m, 0.5H), 8.68(m,0.5H), 8.59(bs, 2H), 8.27(s, 0.5H), 8.05(s, 0.5H), 7.81-7.73(m, 2.5H),7.57(s, 0.5H), 7.54(s, 1H), 7.05(d, 2H, J=8.1), 6.67(d, 2H, J=8.1),4.15(s, 3H), 3.70(s, 8H), 3.63(m, 2H), 2.68(m, 2H), 2.37(t, 2H), 1.84(m,2H)

EXAMPLE 36

NMR(DMSO-d₆) δ: 8.79(bs, 1H), 8.24(s, 1H), 8.16(s, 1H), 7.74(d, 1H),7.62(d, 1H), 7.56(s, 1H), 4.16(s, 3H), 3.59(m, 2H), 2.62(t, 2H)

EXAMPLE 37

(Reaction1)

NMR(DMSO-d₆) δ: 10.13(s, 0.4H), 10.04(s, 0.6H), 8.73(s, 1H), 8.46(s,0.6H), 8.13(s, 0.4H), 7.95(d, 0.6H), 7.90-7.82(m, 1H), 7.67-7.60(m,2.6H), 6.77(d, 2H), 4.29(s, 3H), 3.73(s, 8H)

EXAMPLE 37

(Reaction2)

NMR(DMSO-d₆) δ: 10.62(s, 1H), 10.10(s, 1H), 8.30(s, 1H), 7.91(d, 1H,J=8.8), 7.71(d, 1H, J=8.8), 7.65(d, 3H), 7.59(s, 1H), 7.70-7.20(bs, 4H),6.77(d, 2H), 4.18(s, 3H), 4.13(d, 2H), 3.74(s, 3H)

EXAMPLE 38

(Reaction1)

NMR(DMSO-d₆) δ: 8.68(s, 2H), 8.26(bs, 1H), 7.87(d, 1H), 7.67(bd, 1H)

EXAMPLE 38

(Reaction2)

NMR(DMSO-d₆) δ: 8.85(m, 1H), 8.68(s, 2H), 8.23(s, 0.5H), 8.05(s, 0.5H),7.82(d, 0.5H), 7.62(d, 0.5H), 7.74(m, 1H), 3.55(q, 2H), 2.81(t, 2H)

EXAMPLE 38

(Reaction3)

NMR(DMSO-d₆) δ: 9.12(bs, 2H), 8.88((m, 1H), 8.78(bs, 2H), 8.72(bs, 2H),8.26(s, 0.5H), 8.14(s, 0.5H), 7.82(d, 1H), 7.70(d, 0.5H), 7.60(d, 0.5H),3.65(q, 2H), 2.74(t, 2H)

EXAMPLE 38

(Reaction4)

NMR(DNSO-d₆, 80° C.) δ: 8.89(bs, 2H), 8.48(bs, 2H), 8.10(s, 1H), 7.83(s,1H), 7.74(d, 1H), 7.56(d, 1H), 7.54(s, 1H), 7.06(d, 2H), 6.69(d, 2H),3.69(s, 8H), 2.76-2.37(m, 8H), 1.90(m, 2H)

EXAMPLE 39

NMR(DMSO-d₆) δ: 8.11(s, 1H), 8.00(s, 1H), 7.80-7.45(m, 8H), 3.77(t, 2H),2.79t, 2H)

EXAMPLE 40

(Reaction1)

NMR(DMSO-d₆) δ: 10.08(s, 0.5H), 10.03(s, 0.5H), 8.69(bs, 2H), 83.5(s,0.5H) 8.13(s, 0.5H), 7.87-7.70(m, 2H), 7.60(d, 2H), 6.77(d, 2H), 3.73(s,8H)

EXAMPLE 40

(Reaction2)

NMR(DMSO-d₆) δ: 12.25(s, 1H), 10.31(s, 1H), 8.40(s, 1H), 8.33(s, 1H),8.10(d, 1H, J=8.8), 7.85(d, 1H, J=8.8), 7.69(m, 2H), 7.63(d, 2H, J=8.8),7.60-7.25(bs, 4H), 6.77 (d, 2H), 4.22(d, 2H), 3.74(s, 8H)

EXAMPLE 41

(Reaction1)

NMR(DMSO-d₆) δ: 8.25(m, 2H), 7.90(m, 2H), 7.72(d, 1H), 3.89(s, 3H)

EXAMPLE 41

(Reaction2)

NMR(DMSO-d₆) δ: 8.24(d, 1H), 8.21(s, 1H), 7.95(d, 1H), 7.89((d, 1H),7.71(d, 1H)

EXAMPLE 41

(Reaction3)

NMR(DMSO-d₆) δ: 8.92(t, 1H), 8.27(d, 1H), 8.19(s, 1H), 7.90(d, 1H),7.81(d, 1H) 7.70(d, 1H), 3.53(q, 2H), 2.78(t, 2H)

EXAMPLE 41

(Reaction4)

NMR(DMSO-d₆) δ: 9.11(bs, 2H), 8.88(bs, 1H), 8.71(bs, 2H), 8.22(m, 2H),8.10(s, 1H), 7.86(d, 1H), 7.68(bs, 1H), 3.67(q, 2H), 2.75(t, 2H)

EXAMPLE 41

(Reaction6)

NMR(CD₃ OD) δ: 8.04(s, 1H), 7.73(d, 1H), 7.55(d, 1H), 7.55(d, 1H),7.08(d, 2H), 6.72(d, 1H) 6.65(d, 2H), 3.77(t, 2H), 3.68(t, 4H), 3.61(t,4H), 2.78(t, 2H), 2.61(t, 2H), 2.43(t, 2H), 2.01(m, 2H)

EXAMPLE 42

NMR(DMSO-d₆) δ: 9.08(bs, 2H), 8.77(m, 1H), 8.67(bs, 2H), 8.40(s, 1H),8.07(bs, 0.8H), 8.02(s, 0.2H), 7.76(bs, 1H), 7.70(d, 1H), 7.53(d, 1H),6.82(d, 1H), 3.63m, 2H), 2.72(m, 2H)

EXAMPLE 43

NMR(DMSO-d₆) δ: 8.3-8.15(m, 1H), 7.91(d, 1H), 7.90(m, 1H), 7.71-7.64m,1H), 7.57(d, 1H)

EXAMPLE 44

(Reaction1)

NMR(DMSO-d₆) δ: 14.2-11.3(1H, br), 7.89(1H, d, J=8.2), 7.71(1H d,J=8.2), 7.30(1H, d, J=4.4), 7.08(1H, d, J=4.4), 5.8-2.5(2H, br)

EXAMPLE 44

(Reaction2)

NMR(DMSO-d₆) δ: 8.90(1H, t, J=5.5), 8.16(1H, s), 7.81(1H, d, J=8.1),7.69(1H, d J=8.1), 7.30(1H, d,J=3.7), 7.07(1H, d, J=3.7), 3.54(2H, q,J=5.9), 5.80-3.15(2H, br), 2.82(2H, t, J=6.6)

EXAMPLE 44

(Reaction3)

NMR(DMSO-d₆) δ: 9.06-8.80(2H, br), 8.67-8.45(2H, br), 8.56(1H, m)7.99(1H, s), 7.64(1H, d, J=8.8), 7.48(1H, d, J=8.8), 7.00(1H, d, J=3.7),6.80(1H, d, J=3.7), 3.61(2H, m), 2.66(2H, t, J=6.6)

EXAMPLE 44

(Reaction4)

NMR(DMSO-d₆) δ: 9.05(2H, bs), 8.63(2H, bs), 8.62-8.75(1H, m),8.14-7.92(3H, m), 7.4-7.74(5H, m), 6.96-6.87(1H, m), 6.24(1H, bs),3.56-3.70(2H, m), 2.70(2H, t, J=5.9)

EXAMPLE 45

NMR(DMSO-d₆) δ: 8.25(1H, s), 7.98(1H, bs), 7.69(1H,dd), 7.51(1H, d),6.88(1H, d), 5.93(1H, d), 3.67(2H, t), 2.57(2H, t)

EXAMPLE 46

NMR(DMSO-d₆) δ: 7. (), 6.87(1H, d), 6.66(2H, d), 5.82(1H, d), 2.00(2H,q), 3.77(2H, t), 2.38(2H, t), 2.61(2H, t), 3.4-3.7(8H, m), 2.78(2H, t)

EXAMPLE 47

(Reaction1)

(DMSO-d₆) δ: 8.52(m, 0.5H), 8.46(m, 0.5H), 8.29(s, 1H), 8.24(s, 0.5),8.00(s, 0.5H), 7.78-7.62(m, 1.5H), 7.57(bs, 1.5H), 4.19(s, 3H), 3.30(m,2H), 2.30(t, 2H), 1.80(m, 2H)

EXAMPLE 47

(Reaction2)

(DMSO-d₆) δ: 9.66(s, 1H), 8.56(t, 0.5H), 8.48(t, 0.5H), 8.29(s, 1H),8.26(s, 0.5H), 8.00(s, 0.5H), 7.82-7.71(m, 1.5H), 7.58-7.54(m, 1.5H),7.41(d, 2H), 6.68(d, 2H), 4.19(s, 3H), 3.68(s, 8H), 3.33(m, 2H), 2.34(t,2H), 1.86(m, 2H)

EXAMPLE 47

(Reaction3)

(DMSO-d₆) δ: 10.29(s, 1H), 9.69(s, 1H), 8.5-8.4(m, 1H), 8.19(s, 0.5H),7.95(s, 0.5H), 7.73(d, 0.5H), 7.69(d, 0.5H), 7.59(d, 0.5H), 7.45(d,0.5H), 7.43(d, 2H), 7.27s, 1H), 7.60-7.20(bs, 5H), 6.95(d, 1H), 6.68(d,2H), 4.08(s, 3H), 4.02(s, 2H), 3.68(s, 8H), 3.35(m, 2H), 2.34(t, 2H),1.86(m, 2H)

EXAMPLE 48

(Reaction1)

(CDCl₃) δ: 8.26(d, 1H), 8.07(dd, 1H), 7.32(d, 1H), 2.34(bs, 2H)

EXAMPLE 48

(Reaction2)

(CDCl₃) δ: 8.28(d, 1H), 8.10(dd, 1H), 7.24(d, 1H), 3.75(t, 4H), 3.59(t,4H)

EXAMPLE 48

(Reaction3)

(DMSO-d₆) δ: 10.34(s, 1H), 8.41(bs, 1H), 8.32((d, 1H), 8.03(d, 1H),7.87(d, 1H), 7.87(d, 1H), 7.73(dd, 1H), 7.71(bs, 1H), 7.59(d, 1H),7.37(d, 1H), 4.21(s, 3H), 3.61(t, 4H), 3.50(t, 4H)

EXAMPLE 48

(Reaction4)

(DMSO-d₆) δ: 10.53(s, 2H), 8.30(s, 1H), 8.04(d, 1H), 7.99(d, 1H),7.77(d, 1H), 7.74(dd, 1H), 7.66(t, 1H), 7.48(s, 1H), 7.37(4H+1H),7.18(s, 1H), 4.11(s, 3H), 4.06(d, 2H), 3.62(t, 4H), 3.50(t, 4H)

EXAMPLE 49

(DMSO-d₆) δ: 10.55(s, 1H), 10.50(s, 1H), 8.30-7.13(m, 12H), 4.11(s, 3H),4.07(d, 2H), 3.67(t, 4H), 3.56(t, 4H)

EXAMPLE 50

(Reaction1)

(DMSO-d₆) δ: 10.45(s, 0.5H), 10.38(s, 0.5H), 8.62-7.10)(8H), 4.2 1(s,3H), 3.72(s, 8H)

EXAMPLE 50

(Reaction2)

(DMSO-d₆) δ: 10.58(s, 1H), 10.50(s, 1H), 8.30(s, 1H), 8.19(d, 1H),7.98(dd, 1H), 7.75(d, 1H), 7.64(t, 1H), 7.45(s, 1H), 7.35(4H+1H),7.15(s, 1H), 4.10(s, 3H), 4.07(d, 2H), 3.73(s, 8H)

EXAMPLE 51

(Reaction1)

(CDCl₃) δ: 8.17(d, 1H), 7.54(dd, 1H), 7.39(d, 1H), 3.86-3.23(m, 8H)

EXAMPLE 51

(Reaction2)

(DMSO-d₆) δ: 8.02(d, 1H), 6.84(dd, 1H), 6.61(d, 1H), 4.86(bs, 2H),3.67-3.01(m, 14H)

EXAMPLE 51

(Reaction3)

(CDCl₃) δ: 8.17(d, 1H), 6.71(dd, 1H), 6.50(d, 1H), 4.11-3.22(m, 16H)

EXAMPLE 51

(Reaction4)

(DMSO-d₆) δ: 9.94(d, 1H), 8.30-6.67(m, 8H), 4.20(s, 3H) 3.76(s, 8H),3.52(s, 6H), 3.31(s, 2H)

EXAMPLE 51

(Reaction5)

(DMSO-d₆) δ: 10.36(s, 1H), 9.98(s, 1H), 8.16-6.66(m, 13H), 4.09(s, 3H),4.03(d, 2H), 3.77-3.35(m, 16H)

EXAMPLE 52

(Reaction1)

(CDCl₃) δ: 8.05(d, 1H), 7.68(s, 1H), 7.52(m, 1H), 3.53(q, 2H), 2.54(t,2H), 2.26(s, 6H)

EXAMPLE 52

(Reaction2)

(DMSO-d₆) δ: 8.27(t, 1H), 7.94(d, 1H), 6.80(dd, 1H), 6.58((d, 1H),4.86(bs, 2H), 3.55(s, 8H), 3.27(q, 2H), 2.38(t, 2H), 2.34(s, 6H)

EXAMPLE 52

(Reaction3)

(DMSO-d₆) δ: 8.42(t, 1H), 7.98(d, 1H), 6.95(dd, 1H), 6.77(d, 1H),4.37(t, 4H), 3.90(t, H), 2.27(s, 6H) (comment: Signals of ethylene inthe dimethylaminoethyl residue could not be identified, because theywere overlapped by those of solvent.)

EXAMPLE 52

(Reaction4)

(DMSO-d₆) δ: 10.25(bs, 1H), 9.17(bt, 1H), 8.36(d, 1H), 8.32(d, 1H),8.21(s, 0.5H) 8.09(s, 0.5H), 7.88-7.62(3H), 7.14(d, 1H), 7.03(dd, 1H),4.22(s, 3H), 3.82(s, 8H) 3.69(m, 2H), 3.30(m, 2H), 2.89(s, 6H)

EXAMPLE 52

(Reaction5)

(DMSO-d₆) δ: 10.52(s, 2H), 9.25(bt, 1H), 8.64(bs, 1H), 8.35(d, 1H),8.19(S, 1H), 7.90(d, 1H), 7.78(d, 1H), 7.67(t, 1H), 7.46(s, 1H),7.39(bs, 4H), 7.17(s, 1H), 7.03(d, 1H), 4.11(s, 3H), 4.06(d, 2H),4.00-3.40(m, 10H), 3.32(m, 2H), 2.85(d, 6H)

EXAMPLE 53

(Reaction1)

(DMSO-d₆) δ: 10.12(s, 1H), 10.04(s, 1H), 9.97(s, 1H), 8.32(s, 0.5H),8.25(m, 1H), 8.03(s, 0.5H), 7.80-7.50(m, 4H), 7.40-6.85(bs, 4H), 7.29(s,1H), 6.96(s, 1H), 6.75d, 2H), 4.08(s, 3H), 3.73(s, 8H), 3.34(m, 2H)

EXAMPLE 53

(Reaction2)

(DMSO-d₆) δ: 11.10(s, 1H), 10.20(s, 1H), 8.28(bs, 3H+1H), 7.98(d, 1H),7.89(t, 1H), 7.76(d, 1H), 7.63(d, 2H), 7.54(s, 1H), 7.23(s, 1H),7.65-6.90(bs, 4H), 6.77(d, 2H) 4.12(s, 3H), 4.05(m, 1H), 3.74(s, 8H),3.21(m, 2H), 1.85(m, 2H), 1.57(m, 2H)

EXAMPLE 54

(DMSO-d₆) δ: 10.02(s, 0.5H), 9.95(s, 0.5H), 9.71(s, 1H), 8.32(s, 0.5H),8.01s, 0.5H), 7.80(dd, 1H), 7.66(d, 2H), 7.62(d, 0.5H), 7.49(d, 0.5H),7.33-7.30(m, 6H), 7.03(d, 1H), 6.76(d, 2H), 4.07(s, 3H), 3.73(s, 8H),3.48(s, 2H), 3.00(s, 2H), 2.50-2.45(bd, 8H)

EXAMPLE 55

(DMSO-d₆) δ: 10.05(s, 0.5H), 9.97(s, 0.5H) 9.93(s, 1H), 8.31(s, 0.5H),8.03(s, 0.5H), 7.82(d, 0.5H), 7.79(d, 0.5H), 7.65(m, 2.5H), 7.51(d,0.5H), 7.31(s, 1H), 7.07(s, 6.5H), 7.03(s, 6.5H), 6.75(d, 2H), 4.08(s,3H), 3.73(s, 8H), 3.38(m, 2H), 3.10(m, 4H), 2.73(m, 4H)

EXAMPLE 56

(DMSO-d6) δ: 11.71(s, 1H), 10.20(s, 1H), 8.29(s, 1H), 7.99(d, 1H),7.77(d, 1H), 7.73(s, 2H), 7.67(s, 1H), 7.65(d, 2H), 7.36(s, 1H), 6.77(d,2H), 4.15(s, 3H), 3.74(s, 8H)

EXAMPLE 57

(DMSO-d₆) δ: 10.05(s, 1H), 10.04(s, 0.6H), 9.96(s, 0.4H), 8.31(s, 0.6H),8.02(s, 0.4H), 7.80(m, 1H), 7.64(bs, 3.4H), 7.50(d, 0.6H), 7.27(s, 1H),7.16(s, 1H), 6.88(m, 2H), 6.75(d, 2H), 4.29(t, 2H), 4.08(s, 3H), 3.73(s,8H), 2.77(t, 2H)

EXAMPLE 58

(Reaction1)

(DMSO-d₆) δ: 10.42(bs, 1H), 8.62(t, 1H), 7.89(d, 1H), 7.88(d, 1H),7.59(t, 1H), 2.10(s, 3H)

EXAMPLE 58

(Reaction2)

(DMSO-d₆) δ: 7.30(m, 3H), 6.97(m, 1H), 6.33(bt, 1H), 3.09(m, 2H),1.18(t, 3H)

EXAMPLE 58

(Reaction3)

(CDCl₃) δ: 7.53-7.46(m, 2H), 7.30(t, 1H), 7.00(dd, 1H), 3.84(t, 2H),3.56-3.45(m, 4H), 1.93(bs, 1H), 1.20(t, 3H)

EXAMPLE 58

(Reaction4)

(CDCl₃) δ: 8.21(s, 1H), 8.15-8.03(m, 2H), 7.67(t, 1H), 3.82(s, 4H),3.63(m, 2H), 1.30(t, 3H)

EXAMPLE 58

(Reaction5)

(CDCl₃) δ: 10.32(bs, 2H), 7.25(t, 1H), 6.74-6.67(m, 2H), 6.62(d, 1H),3.82-3.60(m, 4H), 3.42(q, 2H), 1.09(t, 3H)

EXAMPLE 58

(Reaction6)

(DMSO-d₆) δ: 10.10(s, 0.5H), 10.01(s, 0.5H), 8.41-6.44(m, 9H), 4.21(s,3H), 3.74(t, 2H), 3.61(t, 2H), 3.46-3.38(m, 2H), 1.12(t, 3H)

EXAMPLE 58

(Reaction7)

(DMSO-d₆) δ: 10.44(s, 1H), 10.06(s, 0.5H), 9.97(s, 0.5H), 8.35-6.33(m,12H), 4.12 (s, 3H), 3.75(t, 2H), 3.61(t, 2H), 3.49-3.39(m, 2H), 1.13(t,3H)

EXAMPLE 59

(DMSO-d₆) δ: 10.02(s, 0.5H), 9.96(s, 0.5H), 9.92(s, 1H), 8.33(s, 0.5H),8.03(s, 0.5H), 7.82(t, 0.5H), 7.79(d, 0.5H), 7.66(d, 2H), 7.63(d, 0.5H),7.52(d, 05H), 7.36(s, 1H), 7.07(dd, 0.5H), 6.97-6.93(m, 2H), 6.76(d,2H), 6.15(dd, 1H), 4.11(s, 3H), 3.73(s, 8H)

EXAMPLE 60

(DMSO-d₆) δ: 9.97(s, 2H), 8.19(bs, 1H), 7.80(d, 1H), 7.64(d, 2H),7.60(m, 1H), 7.28(s, 1H), 6.93(s, 1H), 6.76(d, 2H), 4.08(s, 3H), 3.73(s,8H), 2.75(t, 2H), 2.56(t, 2H), 2.09(s, 3H)

EXAMPLE 61

(DMSO-d₆) δ: 10.33(s, 0.5H), 10.27(s, 0.5H), 9.99(s, 1H), 8.34(bs, 1H),8.04(bs, 1H), 7.81(d, 1H), 7.73(d, 1H), 7.53(bd, 1H), 7.36(d, 1H),7.28(s, 1H+1H), 6.93(bs, 1H), 4.08(s, 1H), 3.61(t, 4H), 3.50(t, 4H),2.75(t, 2H)2.56(t, 2H), 2.09(s, 3H)

EXAMPLE 62

(Reaction1)

(CDCl₃) δ: 7.95-7.86(m, 2H), 6.95-6.88(m, 1H), 3.91(bs, 4H),3.74-3.69(m, 4H), 2.87(bs, 2H)

EXAMPLE 62

(Reaction2)

(CDCl₃) δ: 8.01-7.91(m, 2H), 6.88(t, 1H), 3.84(t, 4H), 3.68(t, 4H)

EXAMPLE 62

(Reaction3)

(DMSO-d₆) δ: 10.29(bs, 1H), 8.40-7.11(m, 8H), 4.21(s, 3H), 3.66(t, 4H),3.55(t, 4H)

EXAMPLE 62

(Reaction4)

(DMSO-d₆) δ: 10.29(s, 0.5H), 10.22(s, 0.5H), 9.99(s, 1H), 8.33-6.92(m,12H), 4.08(s, 3H), 3.66(t, 4H), 3.55(t, 4H), 2.75(t, 2H), 2.56(t, 2H),2.09(s, 3H)

EXAMPLE 63

(DMSO-d₆) δ: 9.98(s, 1H), 9.64(s, 0.5H), 9.58(s, 0.5H), 8.30(s, 0.5H),8.03(s, 0.5H), 7.83-7.78(m, 1H), 76.5(d, 0.5H), 7.50(d, 0.5H), 7.27(s,1H), 7.15(s, 0.5H), 7.12(s, 0.5H), 6.93(dd, 1H), 6.66(s, 1H), 6.61(d,1H), 4.08(s, 3H), 3.75(s, 8H), 2.75(t, 2H), 2.56(t, 2H), 2.21(s, 3H),2.09(s, 3H)

EXAMPLE 64

(DMSO-d₆) δ: 9.98(s, 1H), 9.64(s, 0.5H), 9.58(s, 0.5H), 8.61(s, 0.5H),8.30(s, 0.5H), 8.03(s, 0.5H), 7.96(m1H), 7.65(d, 1H), 7.50(d, 1H),7.35(dd, 0.5H), 7.27(s, 1H), 6.66(s, 1H), 6.61(d, 1H), 4.08(s, 3H),3.74(s, 8H), 2.75(t, 2H), 2.56(t, 2H) 2.21(s, 3H), 2.09(s, 3H)

EXAMPLE 65

(Reaction1)

(CDCl₃) δ: 8.34(d, 1H), 8.29(dd, 1H), 7.53(d, 1H), 4.69(t, 2H),3.51(m,4),3.41(m, 4H)

EXAMPLE 65

(Reaction2)

(CDCl₃) δ: 8.55(d, 1H), 8.36(dd, 1H), 7.50(d, 1H), 3.61(m, 8H)

EXAMPLE 65

(Reaction3)

(DMSO-d₆) δ: 10.58(bs, 1H), 10.51(bs, 1H), 8.45-7.57(8H), 4.21(s, 3H),3.60(t, 2H), 3.37(t, 4H)

EXAMPLE 65

(Reaction4)

(DMSO-d₆) δ: 10.51(s, 0.5H), 10.44(s, 0.5H), 9.99(s, 1H), 8.37-6.93(8H),4.08(s, 3H), 3.60(t, 4H), 3.37(t, 4H), 2.76(t, 2H), 2.57(t, 2H), 2.10(s,3H)

EXAMPLE 66

(Reaction1)

(CDCl₃) δ: 8.45.(d, 1H), 6.56(d, 1H), 5.02(t, 2H), 4.14(bs, 4H), 3.77(m,4H)

EXAMPLE 66

(Reaction2)

(CDCl₃) δ: 8.49(d, 1H), 6.29(d, 1H), 4.40(t, 4H), 3.87(t, 4H)

EXAMPLE 66

(Reaction3)

(DMSO-d₆) δ: 10.46(s, 0.5H), 10.40(s, 0.5H), 8.45-7.51(m, 6H), 6.52(d,1H), 4.21(s, 3H), 4.13(t, 4H), 3.88(t, 4H)

EXAMPLE 66

(Reaction4)

(DMSO-d₆) δ: 10.39(s, 0.5H), 10.35(s, 0.5H), 9.99(s, 1H), 8.36(s, 0.5H),8.09(s, 0.5H), 7.87-7.82(m, 1H), 7.69(d, 0.5H), 7.55-7.50(m, 1.5H),7.28(s, 1H), 6.95(dd, 1H), 6.52(d, 1H), 4.13(t, 4H), 4.09(s, 3H),3.88(t, 4H), 2.76(t, 2H), 2.57(t, 2H), 2.09(s, 3H)

EXAMPLE 67

(DMSO-d₆) δ: 10.30(s, 1H), 9.99(s, 1H), 8.19(bs, 1H), 7.82((d, 1H),7.64(d, 2H, 8.8), 7.58(m, 1H), 7.29(s, 1H), 6.96(s, 1H), 6.76(d, 2H),4.09(s, 3H), 3.73(s, 8H), 3.54(t, 2H), 2.95(s, 6H), 2.93(m, 2H)

EXAMPLE 68

(DMSO-d₆) δ: 10.32(s, 1H), 10.26(bs, 1H), 8.33-6.97(m, 8H), 4.09(s, 3H),3.66(t, 4H), 3.57-3.51(m, 6H), 2.95-2.90(m, 8H)

EXAMPLE 69

(DMSO-d₆) δ: 10.29(s, 1H), 9.61(bs, 1H), 8.23(bs, 1H), 7.58(bs, 1H),7.52(d, 1H), 7.28(s, 1H), 7.14(d, 1H), 6.95(s, 1H), 6.65(s, 1H), 6.61(d,1H), 4.10(s, 3H), 3.74(s, 8H), 3.54(t, 2H), 2.95(s, 6H), 2.93(t, 2H),2.21(s, 3H)

EXAMPLE 70

(DMSO-d₆) δ: 10.29(s, 1H), 9.64(s, 0.5H), 9.58(s, 0.5H), 8.30-6.55(8H),4.09(s, 3H), 3.74(s, 8H), 3.54(t, 2H), 2.95(s, 6H), 2.93(2H), 2.21(s,3H)

EXAMPLE 71

(DMSO-d₆) δ: 10.53(s, 1H), 10.49(s, 1H), 8.28(1H+1H), 8.13(dd, 1H),7.87(dd, 1H), 7.70(d, 1H), 7.64(d, 1H), 7.34(d, 1H), 7.02(d, 1H),4.10(s, 3H), 3.60(t, 4H), 3.55(t, 2H), 3.37(t, 4H), 2.96(s, 6H)

EXAMPLE 72

(DMSO-d₆) δ: 10.54(s, 1H), 10.43(bs, 1H), 8.26(bs, 1H), 7.90(d, 1H),7.65(d, 1H), 7.52(d, 1H), 7.34(s, 1H), 7.04(s, 1H), 6.52(d, 1H), 4.13(t,4), 4.10(s, 3H), 3.88(t, 4H), 3.56(t, 2H), 2.96(6H+2H)

EXAMPLE 73

(DMSO-d₆) δ: 10.37(s, 1H), 10.33(bs, 1H), 8.23(bs, 1H), 8.04(d, 1H),7.85(dd, 1H), 7.73(dd, 1H), 7.63(d, 1H), 7.37(d, 1H), 7.33(d, 1H),7.00(d, 1H), 4.09(s, 3H), 3.61(t, 4H), 3.60(m, 4H), 3.51(m, 6H), 2.95(s,6H), 2.94(2H)

EXAMPLE 74

(DMSO-d₆) δ: 10.32(s, 1H), 10.26(bs, 1H), 7.83-6.97(m, 8H), 4.09(s, 3H),3.66(t, 4H), 3.55-3.35(m, 6H), 2.94-2.90(m, 8H)

EXAMPLE 75

(DMSO-d₆) δ: 10.56(s, 1H), 9.69(s, 1H), 8.21(s, 1H), 7.87(d, 1H),7.63(d, 1H), 7.36(s, 1H), 7.14(d, 1H), 6.66(s, 1H), 6.62((d, 1H),4.09(s, 3H), 3.75(s, 8H), 3.56(t, 2H), 2.96(2H), 2.21(s, 3H)

EXAMPLE 76

(DMSO-d₆) δ: 10.50(s, 1H), 9.66(s, 0.5H), 9.59(s, 0.5H), 8.30(s, 0.5H),8.05(s, 0.5H), 7.83-7.80(m, 1H), 7.65(d, 0.5H), 7.49(d, 0.5H), 7.23(s,1H), 7.13(d, (d, 1H), 6.99(d, 1H), 6.61(d, 1H), 4.09(s, 3H), 3.74(s,8H), 3.55(t, 2H), 2.96(s, 6H), 2.96(2H), 2.21(s, 3H)

EXAMPLE 77

NMR(DMSO-d₆) δ: 10.07(s, 1H), 9.98(bs, 1H), 8.32-7.63(m, 5H), 7.29(s,1H), 6.95(s, 1H), 6.72(d, 2H), 4.08(s, 3H), 3.73(s, 8H), 3.10(s, 2H),2.17(s, 3H)

EXAMPLE 78

NMR(DMSO-d₆) δ: 10.08(s, 1H), 10.03(s, 0.5H), 9.96(s, 0.5H), 8.33(s,0.5H), 8.03(s, 0.5H), 7.85-7.79(m, 1H), 7.72-7.51(m, 3H), 7.31(s, 1H),7.11(d, 1H) 6.78-6.71(m, 2H), 4.58(s, 2H), 4.10(s, 3H), 3.73(s, 8H),2.97(s, 6H)

EXAMPLE 79

NMR(DMSO-d₆) δ: 10.26(s, 1H), 10.02(s, 0.5H), 9.96(s, 0.5H), 8.50(d,1H), 8.32(s, 0.5H), 8.01(s, 0.5H), 7.83-7.25(m, 8H), 6.95(d, 1H),6.76(d, 2H), 4.07(s, 3H), 3.80(s, 2H), 3.73(s, 8H)

EXAMPLE 80

NMR(DMSO-d₆) δ: 10.27(s, 1H), 10.01(bs, 0.5H), 9.96(bs, 0.5H), 8.52(d,2H), 8.32(bs, 0.5H), 8.02(bs, 0.5H), 7.81(bd, 1H), 7.64(bd, 2H+0.5H),7.51(bd, 0.5H). 7.35(d, 2H), 7.27(s, 1H), 6.94(bs, 1H), 6.76(d, 2H),4.07(s, 3H), 3.73(s, 8H), 3.66(s, 2H)

EXAMPLE 81

NMR(DMSO-d₆) δ: 10.25(s, 1H), 10.02(s, 0.5H), 9.96(s, 0.5H), 8.54(dd,1H), 8.47(d d, 1H), 8.32(s, 0.5H), 8.02(s, 0.5H), 7.83-7.72(m, 2H)7.66(d, 2H), 7.63(d, 0.5H), 7.51(d, 0.5H), 7.36, (dd, 1H), 7.27(s, 1H),6.95(dd, 1H), 6.76(d, 2H), 4.07(s, 3H), 3.73(s, 8H), 3.65(s, 2H)

EXAMPLE 82

NMR(DMSO-d₆) δ: 10.66(s, 1H), 10.01(s, 1H), 9.03(s, 1H), 8.93(d, 1H),8.55(d, 1H), 8.13(s, 0.5H), 8.11(d, 1H). 7.64(d, 2H), 7.63(bs, 1H),7.30((d, 1H), 7.00(s, 1H), 6.76(d, 2H), 4.37(s, 3H), 4.08(s, 3H),3.99(s, 2H), 3.73(s, 8H)

EXAMPLE 83

NMR(DMSO-d₆) δ: 10.36(s, 1H), 10.08(s, 1H), 8.22(bs, 1H), 7.87(d, 1H),7.68(d, 2H), 7.65(d, 1H), 7.37(s, 1H), 7.04(s, 1H), 6.76(d, 2H), 4.09(s,3H), 3.73(s, 8H), 3.45-3.32(m, 2H), 3.10(s, 9H), 2.40(t, 2H), 2.05(m,2H)

EXAMPLE 84

NMR(DMSO-d₆) δ: 9.97(s, 1H), 8.49(bs, 1H), 8.12-7.93(m, 1H),7.71-7.38(m, 2H), 7.26(s, 1H), 7.10(d, 2H,J=8.8), 6.91(s, 1H), 6.69(d,2H,J=8.8), 4.06(s, 3H), 3.70(s, 8H), 3.42-3.33(m, 4H), 2.75(t, 2H),2.56(t, 2H), 2.09(s, 3H)

EXAMPLE 85

NMR(DMSO-d₆) δ: 10.31(s, 0.7H), 9.98(s, 0.3H), 8.47(m, 1H), 8.16(s,0.7H), 7.93(s, 0.3H), 7.73-7.58(m, 1.3H), 7.46(d, 0.7H), 7.27(s, 1H),7.10(d, 2H), 6.93(d, 1H), 6.69(d, 2H), 4.08(s, 3H), 3.70(s, 8H), 3.53(t,2H), 3.42(m, 2H), 2.94(s, 8H), 2.75(m, 2H)

EXAMPLE 86

(Reaction1)

NMR(CDCl₃) δ: 7.98(d, 1H), 6.66(m, 2H), 4.84(d, 2H), 3.56(s, 8H),2.55(s, 3H)

EXAMPLE 86

(Reaction2)

NMR(CDCl₃) δ: 8.11(d, 1H), 6.55(dd, 1H), 6.47(d, 1H), 3.84(t, 4H),3.68(t, 4H), 2.66(s, 3H)

EXAMPLE 86

(Reaction3)

NMR(DMSO-d₆) δ: 9.92(s, 1H), 8.30(d, 1H), 8.29(s, 1H), 7.91(d, 1H),7.70(d, 1H), 7.64(d, 1H), 7.14(d, 1H), 6.66(s, 1H), 6.61(d, 1H), 4.21(s,3H), 3.75(s, 8H), 2.21(s, 3H)

EXAMPLE 86

(Reaction4)

NMR(DMSO-d₆) δ: 10.52(s, 1H), 9.82(s, 1H), 8.28(s, 1H), 7.99(d, 1H),7.75(d,, 1H), 7.64(t, 1H), 7.48(s, 1H), 7.36(bs, 4H), 7.18(s, 1H),7.14(d, 1H), 6.66(s, 1H), 6.62(d, 1H), 4.10(s, 3H), 4.06((1, 2H),3.75(s, 8H), 2.21(s, 3H)

EXAMPLE 87

NMR(DMSO-d₆) δ: 10.27(s, 1H), 9.78(s, 1H), 8.25(s, 1H), 7.96(d, 1H),7.71(d, 1H), 7.44(d, 1H), 7.14(d, 1H), 7.10(s, 1H), 6.67(s, 1H), 6.62(d,1H), 4.08(s, 3H), 3.75(s, 8H), 3.06(m, 2H), 2.75(m, 6H), 2.40(t, 2H),2.21(s, 3H), 1.97(m, 2H)

EXAMPLE 88

NMR(DMSO-d₆) δ: 10.41(s, 1H), 10.01(s, 0.5H), 9.95(s, 0.5H), 8.33(s,1H), 8.03(s, 1H), 7.90(d, 1H), 7.80(t, 1), 7.67-7.61(m, 3H), 7.38(s,1H), 7.24(d, 1H), 7.14-7.11(m, 1H), 6.76(d, 2H), 6.68(dd, 1H), 3.4.11(s,3H), 3.73(s, 8H)

EXAMPLE 89

(Reaction1)

NMR(DMSO-d₆) δ: 8.02(d, 2H), 6.79(d, 2H), 4.86(t, 1H), 3.58(t, 2H),3.51(m, 4H), 1.13(t, 3H)

EXAMPLE 89

(Reaction3)

NMR(DMSO-d₆) δ: 7.24(d, 2H), 6.89(d, 2H), 3.79(m, 4H), 3.42(q, 2H),1.07(t, 3H)

EXAMPLE 89

(Reaction4)

NMR(DMSO-d₆) δ: 10.03(s, 0.5H), 9.96(s, 0.5H), 8.60-7.58(7H), 6.71(d,2H), 4.21(s, 3H), 3.72(bm, 2H), 3.61(bm, 2H), 3.43(q, 2H), 1.10(t, 3H)

EXAMPLE 89

(Reaction6)

NMR(CDCl₃) δ: 7.47(d, 2H), 6.65(d, 2H), 3.63(m, 4H), 3.48(q, 2H),1.21(t, 3H)

EXAMPLE 89

(Reaction7)

NMR(CDCl₃) δ: 7.97(d, 2H), 6.67(d, 2H), 3.63(m, 4H), 3.51(q, 2H),1.22(t, 3H)

EXAMPLE 89

(Reaction8)

NMR(DMSO-d₆) δ: 10.02(s, 0.5H), 9.96(s, 0.5H), 9.92(s, 1H), 8.83(s,0.5H), 8.03(s, 0.5H), 7.81(t, 1H), 7.64(t, 2H), 7.52(d, 0.5H), 7.36(s,1H), 7.07(d, 0.5H), 6.95(d, 1H), 6.76(d, 1H), 6.15(dd, 1H), 4.11(s, 3H),3.73(s, 8H)

EXAMPLE 90

NMR(DMSO-d₆) δ: 10.56(s, 1H), 10.39(bs, 1H), 8.31(s, 1H), 8.03(d, 1H),7.79(d, 3H), 7.67(t, 1H), 7.52(s, 1H), 7.38(bs, 4H), 7.22(s, 1H),7.10(bd, 2H), 4.11(s, 3H), 4.07(d, 2H), 3.73(s, 4H), 3.49(bm, 2H),1.08(t, 3H)

EXAMPLE 91

NMR(DMSO-d₆) δ: 10.37(s, 1H), 10.02(s, 1H), 7.83-6.43(m, 14H), 4.09(s,3H), 4.04(d, 2H), 3.74(t, 2H), 3.61(t, 2H), 1.12(t, 3H)

EXAMPLE 92

(Reaction1)

NMR(CDCl₃) δ: 7.86(dd, 1H), 7.67(d, 1H), 7.00(d, 1H), 3.93(s, 3H),3.80-3.54(m, 8H)

EXAMPLE 92

(Reaction2)

NMR(CDCl₃) δ: 7.85(dd, 1H), 7.74(d, 1H), 6.90(d, 1H), 4.03(s, 3H),3.73(m, 4H), 3.62(m, 4H)

EXAMPLE 92

(Reaction3)

NMR(DMSO-d₆) δ: 10.19(s, 1H), 8.31(s, 2H), 7.88(d, 1H), 7.69(d, 1H),7.59(s, 2H), 7.38(dd, 1H), 7.03(d, 1H), 4.21(s, 3H), 3.82(s, 3H),3.58(t, 4H), 3.45(t, 4H)

EXAMPLE 92

(Reaction4)

NMR(DMSO-d₆) δ: 10.54(s, 1H), 10.38(s, 1H), 8.31(s, 1H), 8.03(d, 1H),7.79(d, 1H), 7.64(t, 1H), 7.60(d, 1H), 7.51(s, 1H), 7.39(dd, 1H),7.37(bs, 4H), 7.21(s, 1H), 7.05(d, 1H), 4.11(s, 3H), 4.06(d, 2H),3.83(s, 3H), 3.59(t, 4H), 3.47(t, 4H)

EXAMPLE 93

(Reaction1)

NMR(DMSO-d₆) δ: 7.98(d, 1H), 6.68(m, 2H), 4.84(t, 2H), 3.56(m, 8H),2.55(s, 3H)

EXAMPLE 93

(Reaction2)

NMR(CDCl₃) δ: 8.11(d, 1H), 6.55(dd, 1H), 6.47(d, 1H), 3.84(t, 4H),3.68(t, 4H), 1.58(s, 3H)

EXAMPLE 93

(Reaction3)

NMR(DMSO-d₆) δ: 9.71(s, 0.5H), 9.64(s, 0.5H), 8.38(s, 0.5H), 8.31(d,1H), 8.11(s, 0.5H), 7.91-7.57(3H), 7.14(d, 1H), 6.67(d, 1H), 6.61(d,1H), 4.21(s, 3H), 3.75(s, 8H), 2.21(s, 3H)

EXAMPLE 93

(Reaction4)

NMR(DMSO-d₆) δ: 10.58(s, 1H), 9.89(s, 1H), 8.31(s, 1H), 8.05(d, 1H),7.79(d,, 1H), 7.67(t, 1H), 7.54(d, 1H), 7.38(bs, 4H), 7.23(d, 1H),7.14(d, 1H), 6.67(s, 1H), 6.62(d, 1H), 4.11(s, 3H), 3.75(s, 8H), 2.21(s,3H)

EXAMPLE 94

NMR(DMSO-d₆) δ:10.23(s, 1H), 10.06(s, 0.4H), 9.98(s, 0.6H), 8.31(s,0.6H), 8.04(s, 0.4H), 7.81(m, 1H), 7.65(m, 2.4H), 7.51(d, 0.6H), 7.30(s,1H), 6.99(s, 0.4H), 6.96(s, 0.6H), 6.75(d, 2H), 4.08(s, 3H), 3.73(s,8H), 3.05(m, 2H), 2.74(s, 6H), 2.40(t, 2H), 1.99(m, 2H)

EXAMPLE 95

(Reaction1)

NMR(DMSO-d₆) δ: 10.02(s, 0.5H), 9.95(s, 0.5H), 9.90(s, 1H), 8.31(s,0.5H), 8.01(s, 0.5H), 7.80(t, 1H), 7.65(d, 2H), 7.62(d, 0.5H), 7.50(d,0.5H), 7.40-7.28(m, 7H), 7.27(s, 1H), 6.95(s, 0.5H), 6.90(s, 0.5H),6.75(d, 2H), 5.02(s, 2H), 4.07(s, 3H), 3.73(s, 8H), 3.04(q, 2H), 2.28(t,2H), 1.72(m, 2H)

EXAMPLE 95

(Reaction2)

NMR(DMSO-d₆) δ: 10.33(s, 1H), 10.22(s, 1H), 8.28(s, 1H), 8.02-7.96(m,4H), 7.76(d, 1H), 7.64(d, 2H), 7.50(s, 1H), 7.16(s, 1H), 6.77(d, 2H),4.08(s, 3H), 3.74(s, 8H), 2.84(q, 2H), 2.42(t, 2H), 1.88(m, 2H)

EXAMPLE 96

NMR(DMSO-d₆) δ: 9.96(bs, 1H), 8.56(s, 1H), 8.30(bs, 0.5H), 7.98(bs,0.5H), 7.79(d, 1H), 7.63(d, 2H), 7.49(m, 1H), 7.09(s, 1H), 6.92(s, 1H),6.76(d, 2H), 4.57(s, 3H), 3.73(s, 8H), 3.60(m, 4H), 3.40(m, 4H)

EXAMPLE 97

(Reaction1)

NMR(DMSO-d₆) δ: 10.30-9.80(bs, 3H), 7.27(t, 1H), 6.76(d, 1H), 6.73(s,1H), 6.63(d, 1H), 3.74(s, 8H)

EXAMPLE 97

(Reaction2)

NMR(DMSO-d₆) δ: 10.15(s, 0.3H), 10.05(s, 0.7H), 8.41(s, 0.7H), 8.31(s,1H), 8.09(s, 0.3H), 7.91-7.79(m, 1H), 7.64-7.59(m, 2H), 7.35-7.14(m,3H), 6.49(d, 1H), 4.21(s, 3H), 3.75(bs, 8H)

EXAMPLE 97

(Reaction3)

NMR(DMSO-d₆) δ: 10.48(s, 1H), 10.22(s, 1H), 8.26(s, 1H), 7.95(d, 1H),7.73(d, 1H), 7.64(t, 1H), 7.45(s, 1H), 7.50-7.14(m, 4H), 7.30(d, 1H),7.23(s, 1H), 7.17(t, 1H), 7.14(s, 1H), 6.51(d, 1H), 4.10(s, 3H), 4.02(d,2H), 3.76(m, 8H)

EXAMPLE 98

NMR(DMSO-d₆) δ: 10.60(s, 1H), 10.10(s, 1H), 8.22(s, 1H), 7.87(d, 1H),7.65(d, 2H), 7.63(s, 1H), 7.35(s, 1H), 7.04(s, 1H), 6.76(d, 2H), 4.09(s,3H), 3.73(s, 8H), 3.56(t, 2H), 2.96(s+t, 8H)

The present invention will hereinafter be described by the followingexamples. It is however borne in mind that the present invention is notlimited to or by the following examples. Each Compound No. indicated inparentheses after Example No. corresponds to Compound No. shown inTables 1-4.

Referential Preparation 1

Methyl 3,4-diaminobenzoate

3,4-Diaminobenzoic acid (3.0 g) was suspended in methanol, followed bythe dropwise addition of 1.86 ml of thionyl chloride. Thionyl chloridewas added twice, in an amount of 0.5 ml each time, and the resultingmixture was heated under reflux for 10 hours and 40 minutes. The thionylchloride and methanol were distilled out, followed by the dissolution ofthe residue in methylene chloride. The solution so formed was washedwith a 0.5N aqueous solution of sodium hydroxide and then with asaturated aqueous solution of sodium chloride, and was dried over sodiumsulfate. The solvent was distilled out. The residue was washed withn-hexane and then dried, whereby 3.04 g of the target compound wereobtained (yield: 93%).

Referential Preparation 2

(Reaction 1)

3- N,N-Bis(2-hydroxyethyl)amino!nitrobenzene

3-Aminobenzene (5.0 g; 36.2 mmol) was dissolved in 36 ml of 30% aceticacid, followed by the addition of 22.9 ml of ethylene oxide under icecooling. The resulting mixture was stirred overnight at roomtemperature. The reaction mixture was extracted with ethyl acetate. Theethyl acetate solution was dried over sodium sulfate and thenconcentrated. The residue was washed with ethyl ether, whereby 5.21 g(23.0 mmol) of the title compound were obtained as yellow crystals(yield: 63.6%).

m.p. 98.5°-100° C.

(Reaction 2)

3- N,N-Bis(2-chloroethyl)amino!nitrobenzene

3- N,N-Bis(2-hydroxyethyl)amino!nitrobenzene (2.5 g; 11.0 mmol) wassuspended in 25 ml of toluene, followed by the addition of 10.2 g (85.7mmol; 7.8 equivalents) of thionyl chloride under ice cooling. Theresultant mixture was heated for 5 hours over an oil bath controlled at70° C. The reaction mixture was concentrated under reduced pressure.Ethyl acetate and water were added to the residue so that the residuewas dissolved. The resulting mixture was allowed to separate into twolayers. The ethyl acetate layer, that is, the ethyl acetate extract wasdried over sodium sulfate and then concentrated under reduced pressure.The residue was washed with ethyl ether, whereby 2.67 g (10.1 mmol) ofthe title compound were obtained as yellow crystals (yield: 92.2%).

m.p. 112°-113° C.

(Reaction 3)

N,N-Bis(2-chloroethyl)-1,3-phenylenediamine hydrochloride

3- N,N-Bis(2-chloroethyl)amino!nitrobenzene (2.0 g; 7.6 mmol) wasdissolved in 35 ml of concentrated hydrochloric acid, followed by theaddition of 6.9 g (30.6 mmol; 4.0 equivalents) of tin(II) chloridedihydrate. The resultant mixture was stirred under heating for 1 hourover an oil bath controlled at 100° C. The reaction mixture was allowedto cool down to room temperature and then diluted with water. Theresulting mixture was basified with concentrated aqueous ammonia andthen extracted twice with ethyl acetate. The extracts were combined,dried over sodium sulfate and then concentrated under reduced pressure.The residue was added with 4N hydrochloric acid/dioxane, followed byconcentration. The residue was crystallized from a mixed solvent of asmall amount of methanol and ethyl ether, whereby 1.97 g (7.3 mmol) ofthe title compound were obtained as yellow crystals (yield: 96.1%).

m.p. 195°-201° C.

EXAMPLE 1

(Compound No. 3017)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid

(Reaction 1)

1-Methyl-4-nitropyrrol-2-carboxyaldehyde

A solution of 25 g (0.23 mol) of 1-methylpyrrole-2-carboxyaldehyde in200 ml of acetic anhydride was cooled to -40° C. Fuming nitric acid(17.6 g) was added dropwise to the solution over 30 minutes, followed bystirring at -40° C. for 1 hour and at -10° C. for additional 2 hours.The reaction mixture was added with ice and allowed to stand over night.The reaction mixture was extracted with ethyl acetate and thenneutralized with sodium hydrogencarbonate. The solvent was thendistilled out under reduced pressure. The residue was purified bychromatography on a silica gel column (ethyl acetate/n-hexane =1/2) andthen crystallized from a 5:1 mixture of ethanol and water, whereby 5.67g of the title compound were obtained as brown crystals (yield: 16%).

(Reaction 2)

Methyl 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylate

A solution of 3.0 g (19.5 mmol) of1-methyl-4-nitropyrrole-2-carboxyaldehyde and 3.4 g (20.5 mmol) ofmethyl 3,4-diaminobenzoate in 300 ml of nitrobenzene was heated underreflux at 150°-160° C. for 32 hours. After completion of the reaction,the precipitated particles were collected by filtration and then washedwith 100 ml of IPA, whereby 4.79 g of the title compound were obtainedas yellow powder (yield: 81.9%).

IR(KBr)cm⁻¹ : 3246, 1691, 1628, 1300, 751.

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid

A solution of 4.4 g of potassium hydroxide in 30 ml of water was addedto a solution of 4.7 g (15.6 mmol) of methyl1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylate in 30 mlof ethanol, followed by stirring at 85° C. for 2.5 hours. Aftercompletion of the reaction, the reaction mixture was acidified withconcentrated hydrochloric acid while the mixture was still warm. Theresultant mixture was allowed to cool down to room temperature. Theprecipitated particles were then collected by filtration. Theprecipitated particles were washed with water and then with ethanol, andthereafter dried, whereby 4.1 g of the title compound were obtained aspale yellow powder (yield: 92.4%).

IR(KBr)cm⁻¹ : 3133, 1655, 1625, 1310, 1120.

EXAMPLE 2

(Compound No. 318)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide

CDI (448 mg; 2.76 mmol) was added to a solution of 608 mg (2.13 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid in 18ml of DMF, followed by stirring at room temperature for 30 minutes.2-Aminopropionitrile (446 mg; 6.38 mmol) was added dropwise, followed bystirring at room temperature for 30 minutes. The reaction mixture wasconcentrated, followed by the addition of ethanol. The precipitatedcrystals were collected by filtration, whereby 360 mg of the titlecompound were obtained as pale yellow crystals (yield: 50%).

(Reaction 2)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide (1.8 g; 5.32 mmol) was suspended in 100 mlof ethanol. Hydrogen chloride gas was bubbled at 0° C. through thesuspension under stirring for 30 minutes. After the resultant mixturewas stirred further at room temperature for 1 hour with hydrogenchloride gas bubbled therethrough, nitrogen gas was bubbled to purgeexcess hydrogen chloride gas. The reaction mixture was concentratedunder reduced pressure and the residue was washed with ethyl ether. Theresidue was again suspended in 60 ml of a 1:1 mixed solvent of ethanoland methanol, followed by stirring with ammonia gas bubbledtherethrough. After completion of the reaction, nitrogen gas was bubbledto purge excess ammonia gas and the resulting mixture was evaporated todryness under reduced pressure. The residue was added with IPA and aninsoluble matter was collected by filtration, whereby 2.0 g of yellowpowder were obtained (yield: 95.9%).

(Reaction 3)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (200 mg; 0.51 mmol) wasdissolved in 12 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 0.7 ml of 1N hydrochloric acid and180 mg of 5% Pd/C. The reactor was purged with nitrogen gas. Theresulting mixture was stirred under a hydrogen gas atmosphere at roomtemperature for 2 hours. After completion of the reaction, the reactorwas purged again with nitrogen gas. The 5% Pd/C was filtered off and themethanol was distilled out under reduced pressure. The resultingsolution was cooled to 0° C., to which 0.17 ml of triethylamine wasadded under a nitrogen gas atmosphere. The solution so obtained wasadded with a solution of N-formylimidazole (5 equivalents) in 5 ml oftetrahydrofuran, which had been prepared right before by adding 410 mg(2.53 mmol) of CDI to a solution of 0.1 ml (2.53 mmol) of formic acid in5 ml of tetrahydrofuran and then stirring the resultant mixture at roomtemperature for 15 minutes!. The thus-obtained solution was stirred, aswas, for 30 minutes. The solvent was distilled out under reducedpressure and the residue was purified by chromatography on a silica gelcolumn (ethyl acetate/IPA/water=5/2/1), whereby 187 mg of white powderwere obtained (yield: 94%).

IR(KBr)cm⁻¹ : 3276, 2938, 2363, 1636, 1542, 1519, 1473, 1312.

Elemental analysis for C₃₀ H₃₆ N₈ O₂ Cl₂.HCl.0.5H₂ O: Calculated: C,54.84; H, 5.83; N, 17.05 Found: C, 55.07; H, 6.14; N, 16.98

EXAMPLE 3

(Compound No. 4)

1H-2- 4- 4- 4-N,N-bis(2-chloroethyl)amino!phenyl!butylylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Triethylamine (164 mg; 1.62 mmol) was added to a solution of 645 mg(1.62 mmol) of 1H-2-(4-amino-1-methyl-2-pyrrole)benzimidazole-5-N-(2-amidinoethyl)!carboxamide dihydrochloride, 739 mg (2.43 mmol) ofchlorambucil, 601 mg (2.91 mmol) of DCC and a catalytic amount of DMAPin 19 ml of DMF, followed by stirring at room temperature for 3 hours.After completion of the reaction, the precipitated crystals werefiltered off and the filtrate was concentrated. The residue wassubjected to flush column chromatography (ethylacetate/IPA/water=6/2/1), whereby 170 mg of the title compound wereobtained as pale red crystals.

m.p.≧289° C. (dec.).

IR(KBr)cm⁻¹ : 3276, 2939, 2363, 1637, 1542, 1519, 1474.

Elemental analysis for C₃₀ H₃₆ N₈ O₂ Cl₂ HCl Calculated: C, 55.60; H,5.75; N, 17.29 Found: C, 55.27; H, 6.14; N, 16.98

EXAMPLE 4

(Compound No. 1)

1H-2- 4- 4-N,N-bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (500 mg; 1.28 mmol; seeReaction 2 in Example 2) was dissolved in a 1:1 mixed solvent of DMF andmethanol in a reactor, followed by the addition of 250 mg of 5% Pd/C.The reactor was purged with nitrogen gas. The resulting mixture wasstirred under a hydrogen gas atmosphere at room temperature for 2 hoursand then at 40° C. for additional 1 hour. After completion of thereaction, the reactor was purged again with nitrogen gas. The Pd/C wasfiltered off and the methanol was distilled out under reduced pressure.The resulting solution was cooled to -40° C. Under a nitrogen gasatmosphere, the solution so obtained was added dropwise with a solutionof 4- N,N-bis(2-chloroethyl)amino!benzoyl chloride (1.1 equivalents) in5 ml of methylene chloride, said solution having been prepared rightbefore. The thus-obtained solution was stirred for 30 minutes and wasthen allowed to stand overnight. The solvent was distilled out underreduced pressure and the residue was purified by chromatography on asilica gel column (ethyl acetate/IPA/water=6/2/1), whereby 91 mg ofwhite powder were obtained.

IR(KBr)cm⁻¹ : 3329, 2361, 1692, 1607, 1545, 1281, 759.

Elemental analysis for C₂₇ H₃₁ N₈ O₂ Cl₃.2H₂ O: Calculated: C, 50.51; H,5.50; N, 17.45 Found: C, 50.37; H, 5.39; N, 17.20

EXAMPLE 5

(Compound No. 326)

1H-2-(4-Benzoylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (216 mg; 5.51 mmol) wasdissolved in 20 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 200 mg of 5% Pd/C. Under a hydrogengas atmosphere, the resulting mixture was stirred at room temperaturefor 3 hours. After completion of the reaction, the reactor was purgedagain with nitrogen gas, the Pd/C was filtered off, and the methanol wasdistilled out under reduced pressure. The solution was cooled to 0° C.and under a nitrogen gas atmosphere, a solution of benzoyl chloride (1.1equivalents) in 5 ml of methylene chloride was added dropwise. Thesolution was stirred for 30 minute and was then allowed to standovernight. After the solvent was distilled out under reduced pressure,the residue was purified by chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1), whereby 50 mg of white powder were obtained(yield: 19.5%).

IR(KBr)cm⁻¹ : 3294, 1690, 1638, 1552, 1309, 708.

EXAMPLE 6

(Compound No. 341)

1H-2-(4-(Guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!dicarboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (33.1 mg; 0.0842 mmol) wasdissolved in 8.3 ml of a 1:1 mixed solvent of methanol and DMF. Using16.0 mg of 10% Pd/C, the reactant was hydrogenated at room temperatureso that it was converted to its corresponding amino derivative. Then,38.9 mg (0.253 mmol) of guanidinoacetic acid hydrochloride and 53.9 mg(0.261 mmol) of DCC were added. The resulting mixture was stirred atroom temperature for one day and then concentrated. The residue waspurified by flush column chromatography (ODS, methanol-water), whereby19.5 mg of the title compound were obtained as colorless crystals(yield: 47%).

m.p. 180°-187° C. (dec.).

IR(KBr)cm⁻¹ : 3398, 1648, 1561, 1399, 1320, 1236.

Elemental analysis for C₁₉ H₂₄ N₁₀ O₂ 2HCl Calculated: C, 45.88; H,5.27; N, 28.16 Found: C, 45.83; H, 5.00; N, 28.02

EXAMPLE 7

(Compound No. 340)

1H-2-(4-Guanidinoacetylamino-1-methylpyrrol-2-yl)benzimidazole-5-(N-(3-dimethylaminopropyl)!carboxamidehydrochloride

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide

CDI (30.3 mg; 0.187 mmol) was added to a solution of 44.5 mg (0.155mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylicacid in 1.3 ml of DMF, followed by stirring at room temperature for 30minutes. The resultant mixture was concentrated, to which ethanol wasadded. The precipitated crystals were collected by filtration, whereby43.8 mg of the title compound were obtained as pale yellow crystals(yield: 76%).

m.p. 244°-246° C.

(Reaction 2)

1H-2-(4-Guanidinoacetylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide hydrochloride

10% Pd/C (6.8 mg) was added to a solution of 13.2 mg (0.0356 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide in 1.4 ml of a 1:1 mixed solventof methanol and DMF, followed by hydrogenation at room temperature. ThePd/C was filtered off and the filtrate was washed with DMF. Under anitrogen gas atmosphere, 16.4 mg of guanidine acetate hydrochloride and22.8 mg (0.110 mmol) of DCC were added to the filtrate. The resultingmixture was stirred under shading at room temperature for 30 minutes andwas then concentrated. The residue was subjected to flush columnchromatography (ODS:methanol/water=0/1→1/10). Relevant fractions wereconcentrated to obtain crystals. The crystals were dissolved in methanoland, after an insoluble matter was filtered off, the filtrate wasconcentrated again, whereby 9.5 mg of the title compound were obtainedas colorless crystals (yield: 56%).

m.p. 190°-195° C. (dec.).

EXAMPLE 8

(Compound No. 321)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide hydrochloride

Formic acid (186 mg; 4.03 mmol) was added dropwise to a THF solution of653 mg (4.03 mmol) of CDI, followed by stirring for 15 minutes. Theresultant mixture was added dropwise at -40° C. to a solution of 0.805mmol of 1H-2-(1-methyl-4-aminopyrrol-2-yl)benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide in a mixed solvent of methanol andDMF. The thus-obtained mixture was stirred at room temperature for 15minutes and then concentrated. The concentrate was fractionated bychromatography on a silica gel column (methanol/chloroform/aqueousammonia). An oil so obtained was treated with IPA and ethyl acetate andfurther with 4N hydrochloric acid, whereby 240 mg of the title compoundwere obtained as colorless crystals (yield: 74%).

m.p. 123°-128° C. (dec.).

EXAMPLE 9

(Compound No. 84)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!phenylbutyrylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide hydrochloride

Following the procedures of Example 3,1H-2-(4-amino-1-methylpyrrol-2-yl)benzimidazole-5-N-(3-dimethylaminopropyl)!carboxamide hydrochloride and chlorambucilwere bonded together to obtain the title compound.

m.p. 134°-140° C.

IR(KBr)cm⁻¹ : 3424, 3282, 2955, 1655, 1648, 1579, 1519, 1460.

EXAMPLE 10

(Compound No. 320)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(3,4,5-trimethoxyphenyl)!carboxamide

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(3,4,5-trimethoxyphenyl)!carboxamide

In 40 ml of DMF, 233 mg (0.814 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid, 218mg (1.06 mmol) of DCC and 132 mg (0.977 mmol) of HOBt were stirred for 1hour at room temperature. The reaction mixture was concentrated,followed by the addition of methanol. The precipitated crystals werecollected by filtration, whereby 360 mg of the title compound wereobtained as pale yellow crystals (yield: 50%).

(Reaction 2)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(3,4,5-trimethoxyphenyl)!carboxamide

10% Pd/C was added to a solution of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(3,4,5-trimethoxyphenyl)!carboxamide in 30 ml of a 1:1 mixed solventof DMF and methanol, followed by stirring at room temperature for 3hours. The corresponding amino derivative was obtained and following theprocedures of Example 8, was then formylated, whereby 100 mg of thetitle compound were obtained as colorless crystals (yield: 41%).

m.p. 177°-182° C.

IR(KBr)cm⁻¹ : 3449, 3309, 1655, 1610, 1509, 1466, 1409, 1315.

EXAMPLE 11

(Compound No. 339)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-(N-stearyl)carboxamide

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-stearyl)carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.20g; 0.68 mmol) was dissolved in 5 ml of DMF, followed by the addition of0.12 g (0.74 mmol; 1.1 equivalents) of CDI. The thus-obtained mixturewas stirred under a nitrogen gas atmosphere at room temperature for 2hours. The reaction mixture was ice-cooled, followed by the addition of0.20 g (0.74 mmol; 1.1 equivalents) of stearylamine. The temperature ofthe resultant mixture was allowed to rise back to room temperature, atwhich the mixture was stirred for 3.5 hours and was then allowed tostand overnight. DMF (5 ml) was added further, followed by stirring for10 hours. The resulting solid was collected by filtration and thenwashed with methanol, whereby 0.23 g (0.45 mmol) of the title compoundwas obtained as yellow crystals (yield: 65.8%).

m.p. 142°-144° C.

(Reaction 2)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl)benzimidazole-5-(N-stearyl)carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-stearyl)carboxamide(0.22 g; 0.43 mmol) was suspended in a mixed solvent of 5 ml of DMF and5 ml of methanol, followed by the addition of 0.5 ml of 1N hydrochloricacid. Using 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure so that the reactant was converted to its correspondingamino derivative. A solution of half the amino derivative in DMF wasstirred under a nitrogen gas atmosphere and ice cooling, to which 68 μl(0.49 mmol; 2.0 equivalents) of triethylamine were added. To thethus-obtained mixture, a solution of 4-N,N-bis(2-chloroethyl)amino!benzolyl chloride, which had beensynthesized from 0.07 g (0.27 mmol) of 4-N,N-bis(2-chloroethyl)amino!benzoic acid, in 2 ml of dichloromethane wasadded dropwise. The temperature of the resultant mixture was allowed torise back to room temperature, at which the mixture was stirred for 3.5hours and was then allowed to stand overnight. The mixture wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (eluted with methylenechloride/2-4% methanol) and then crystallized from methylenechloride-water, whereby 36 mg (0.048 mmol) of the title compound wereobtained as light brown crystals (yield: 22.3%).

m.p. 173°-177° C.

IR(KBr)cm⁻¹ : 3422, 2923, 1636, 1541, 1473.

Elemental analysis for C₄₂ H₆₀ N₆ O₂ Cl₂.H₂ O: Calculated: C, 65.52; H,8.12; N, 10.92; Cl, 9.21 Found: C, 65.87; H, 8.24; N, 10.53; Cl, 9.21

EXAMPLE 12

(Compound No. 337)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-(N-stearyl)carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-stearyl)carboxamide(0.22 g; 0.43 mmol) was suspended in a mixed solvent of 5 ml of DMF and5 ml of methanol, followed by the addition of 0.5 ml of 1N hydrochloricacid. Using 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure so that the reactant was converted to its correspondingamino derivative. Half of the DMF solution of the amino derivatives wasstirred under a nitrogen gas atmosphere and ice cooling, to which 68 μl(0.49 mmol; 2.0 equivalents) of triethylamine were added. To thethus-obtained mixture, a solution of 1-formylimidazole, which had beenprepared from 0.17 g (1.05 mmol; 5.0 equivalents) of CDI and 40 μl (1.06mmol; 5.0 equivalents) of formic acid, in THF was added dropwise. Thetemperature of the resultant mixture was allowed to rise back to roomtemperature, at which the mixture was stirred for 5 hours and was thenallowed to stand overnight. The mixture was concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluted with methylene chloride/4-8% methanol) and thencrystallized from ethyl ether-water, whereby 57 mg (0.11 mmol) of thetitle compound were obtained as light brown crystals (yield: 48.4%).

m.p. 160°-163° C.

IR(KBr)cm⁻¹ : 3368, 2918, 1654, 1541, 1472.

Elemental analysis for C₃₂ H₄₉ N₅ O₂.1.5H₂ O: Calculated: C, 68.29; H,9.31; N, 12.44 Found: C, 68.18; H, 9.03; N, 12.38

EXAMPLE 13

(Compound No. 14)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)aminomethyl!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-(N-(2-amidinoethyl)!carboxamidehydrochloride

(Reaction 1)

Methyl 4-chloromethylbenzoate

A solution of 2.0 g (12 mmol) of 4-chloromethylbenzoic acid in 50 ml ofmethanol was added with 5 droplets of concentrated sulfuric acid,followed by stirring under heat and reflux for 4 days. Afterneutralization with a 5% aqueous solution of sodium carbonate, theresultant mixture was extracted with chloroform. The chloroform extractwas dried over magnesium sulfate and then concentrated under reducedpressure, whereby 1.7 g of a colorless liquid were obtained.

IR(KBr)cm⁻¹ : 2953, 1720, 1281, 1106, 713.

(Reaction 2)

Methyl 4- N,N-bis(2-hydroxyethyl)aminomethyl!benzoate

A solution of 1.7 g (9.2 mmol) of methyl 4-chloromethylbenzoate in 25 mlof chloroform was added with 10 g (95 mmol) of diethanolamine, followedby heating under reflux for 10 hours. The resulting solution was washedwith water and then dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform), whereby 1.5 g of acolorless oil were obtained.

IR(KBr)cm⁻¹ : 3384, 2952, 1721, 1283, 754.

(Reaction 3)

Methyl 4- N,N-bis(2-chloroethyl)aminomethyl!benzoate

Thionyl chloride (5 ml) was added to 1.5 g (5.9 mmol) of methyl 4-N,N-bis(2-hydroxyethyl)aminomethyl!benzoate, followed by stirring at 50°C. for 2 hours. After excess thionyl chloride was distilled out underreduced pressure, methylene chloride was added again. Distillation wasrepeated twice under reduced pressure, whereby 9.5 g of a colorless oilwere obtained.

(Reaction 4)

4- N,N-Bis(2-chloroethyl)aminomethyl!benzoic acid

Concentrated hydrochloric acid (50 ml) was added to 9.5 g (32.7 mmol) ofmethyl 4- N,N-bis(2-chloroethyl)aminomethyl!benzoate, followed bystirring under heating and reflux for 2 hours. After the solvent wasdistilled out under reduced pressure, the residue was washed withacetone, whereby 8.5 g of white powder were obtained.

IR(KBr)cm⁻¹ : 3409, 2917, 1713, 1220, 1108, 752.

(Reaction 5)

4- N,N-Bis(2-chloroethyl)aminomethyl!benzoyl chloride

Thionyl chloride (1 ml) was added to a solution of 320 mg (1.0 mmol) of4- N,N-bis(2-chloroethyl)aminomethyl!benzoic acid in 2 ml of benzene,followed by stirring under heating at 80° C. for 2 hours. After thesolvent was distilled out under reduced pressure, the residue was driedup under reduced pressure so that a white solid was obtained.

(Reaction 6)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)aminomethyl!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-aminodiethyl)!carboxamide hydrochloride was dissolved in 20 ml of a1:1 mixed solvent of DMF and methanol in a reactor, followed by theaddition of 1 ml of 1N hydrochloric acid and 250 mg of 5% Pd/C. Thereactor was purged with nitrogen gas. Under a hydrogen gas atmosphere,the reaction mixture was stirred at room temperature for 2 hours. Aftercompletion of the reaction, the reactor was purged again with nitrogengas. The Pd/C was filtered off and the methanol was distilled out underreduced pressure. The resultant solution was cooled to 0° C. and, after350 μl of triethylamine were added under a nitrogen gas atmosphere, asolution of 4- N,N-bis(2-chloroethyl)aminomethyl!benzoyl chloride (1.1equivalents) in 5 ml of DMF was added dropwise. After the resultantsolution was stirred, as was, for 3 hours, methanol was added, followedby further stirring for 30 minutes. After the solvent was distilled outunder reduced pressure, the residue was purified by chromatography on asilica gel column (ethyl acetate/IPA/water/acetic acid=5/2/1/1), whereby110 mg of white powder were obtained.

IR(KBr)cm⁻¹ : 3328, 1688, 1560, 1404, 1027, 674.

EXAMPLE 14

(Compound No. 334)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-(N-butyl)carboxamid

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-butyl)carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.30g; 1.05 mmol) was dissolved in 10 ml of DMF, followed by the addition of0.20 g (1.23 mmol; 1.2 eq.)) of CDI. The thus-obtained mixture wasstirred under a nitrogen gas atmosphere at room temperature for 2 hours.The mixture was ice-cooled, to which 0.11 ml (1.11 mmol; 1.1equivalents) of butylamine was added. The temperature of thethus-obtained mixture was allowed to rise back to room temperature, atwhich the mixture was stirred for 3 hours and then allowed to standovernight. The reaction mixture was concentrated under reduced pressureand the residue was washed with IPA, whereby 0.26 g (0.76 mmol) of thetitle compound was obtained as yellow crystals (yield: 72.8%).

m.p. 229°-230° C.

(Reaction 2)

1H-2-(4-Formylamino-1-methylpyrrol-2-yl)benzimidazole-5-(N-butyl)carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-butyl)carboxamide(0.24 g; 0.71 mmol) was suspended in a mixed solvent of 5 ml of DMF and5 ml of methanol, followed by the addition of 0.7 ml of 1N hydrochloricacid. Using 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure so that the reactant was converted to its correspondingamino derivative. Half of the DMF solution of the amino derivative wasstirred under a nitrogen gas atmosphere and ice cooling, to which 49 μl(0.35 mmol; 1.0 equivalent) of triethylamine were added. To thethus-obtained mixture, a solution of 1-formylimidazole, which had beenprepared from 0.28 g (1.73 mmol; 5.0 equivalents) of CDI and 66 μl (1.75mmol; 5.0 equivalents) of formic acid, in THF was added dropwise. Thetemperature of the resultant mixture was allowed to rise back to roomtemperature, at which the mixture was stirred for 4 hours and was thenallowed to stand overnight. The mixture was concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (methylene chloride/5-8% methanol) and then crystallized fromethyl ether, whereby 78 mg (0.23 mmol) of the title compound wereobtained as white purple crystals (yield: 65.7%).

m.p. 228°-230° C.

IR(KBr)cm⁻¹ : 3277, 2960, 1677, 1610, 1560, 1290, 1128.

Elemental analysis for C₁₈ H₂₁ N₅ O₂.0.2H₂ O:

Calculated: C, 63.03; H, 6.29; N, 20.42 Found: C, 62.71; H, 6.07; N,20.20

EXAMPLE 15

(Compound No. 336)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-(N-butyl)carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-butyl)carboxamide(0.24 g; 0.71 mmol) was suspended in a mixed solvent of 5 ml of DMF and5 ml of methanol, followed by the addition of 0.7 ml of 1N hydrochloricacid. Using 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure so that the reactant was converted to its correspondingamino derivative. Half of the DMF solution of the amino derivative wasadded with 49 μl (0.35 mmol 1.0 equivalent) of triethylamine, 0.10 g(0.38 mmol; 1,1 equivalents) of 4- N,N-bis(2-chloroethyl)amino!benzoicacid and 52 mg (0.38 mmol; 1.1 equivalents) of HOBt. The resultantmixture was ice-cooled under a nitrogen gas atmosphere, followed by theaddition of 79 mg (0.38 mmol; 1.1 equivalents) of DCC. The temperatureof the resultant mixture was allowed to rise back to room temperature,at which the mixture was stirred for 4 hours and was then allowed tostand overnight. The mixture was concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column(methylene chloride/4% methanol) and then crystallized from ethyl ether,whereby 90 mg (0.16 mmol) of the title compound were obtained as paleyellow crystals (yield: 42.6%).

m.p. 190°-192° C.

IR(KBr)cm⁻¹ : 3390, 2925, 1655, 1518, 1458, 1328, 815.

Elemental analysis for C₂₆ H₂₉ N₉ O₂ Cl₂.HCl.2H₂ O: Calculated: C,48.57; H, 5.33; N, 19.61; Cl, 16.54 Found: C, 48.38; H, 5.22; N, 19.26;Cl, 16.36

EXAMPLE 16

(Compound No. 305)

1H-2- 4- 2-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Ethyl 2- N,N-bis(2-hydroxyethyl)amino!benzoate

Ethylene oxide (12 ml; 242 mmol) was added dropwise under ice cooling toa solution of 4.1 g (25 mmol) of ethyl 2-aminobenzoate in 25 ml of a 30%suspension of acetic acid, followed by stirring for 1 hour. After theresultant mixture was stirred at room temperature for 2 nights, themixture was stirred for 2 hours while bubbling nitrogen gastherethrough. Sodium hydrogencarbonate was added to the mixture toneutralized the same. Sodium chloride was then added until saturation,followed by extraction with ethyl acetate. The extract was dried overmagnesium sulfate and the solvent was distilled out under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (n-hexane/ethyl acetate=1:1→0:1), whereby 3.4 g of a pale yellowoil were obtained (yield: 53%).

IR(KBr)cm⁻¹ : 3421, 2957, 1699, 1252, 1078, 764.

(Reaction 2)

Ethyl 2- N,N-bis(2-chloroethyl)amino!benzoate

Thionyl chloride (0.8 ml; 11.0 mmol) was added to a solution of 1.0 g(4.0 mmol) of ethyl 2- N,N-bis(2-hydroxyethyl)amino!benzoate in 5 ml ofmethylene chloride, followed by stirring at room temperature for 1 hour.After the solvent was distilled out under reduced pressure, methylenechloride was added again in a small amount and was then distilled outunder reduced pressure. This procedure was repeated twice. The resultantmixture was concentrated under reduced pressure, whereby 950 mg of abrown oil were obtained (yield: 83%).

(Reaction 3)

2- N,N-Bis(2-chloroethyl)amino!benzoic acid

Ethyl 2- N,N-bis(2-chloroethyl)amino!benzoate (950 mg; 3.3 mmol) wasadded to 15 ml of concentrated hydrochloric acid, followed by stirringfor 8 hours under heating and reflux. The solvent was distilled outunder reduced pressure and the residue was purified by chromatography ona silica gel column (methylene chloride→acetone), whereby 520 mg ofwhite powder were obtained (yield: 61%).

IR(KBr)cm⁻¹ : 3433, 1695, 1467, 1131, 776.

(Reaction 4)

1H-2- 4- 2-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-(N-(2-amidinoethyl)!carboxamide hydrochloride (300 mg; 0.77 mmol) wasdissolved in 25 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 850 μl of 1N hydrochloric acid and250 mg of 5% Pd/C. The reactor was purged with nitrogen gas. Theresulting mixture was stirred under a hydrogen gas atmosphere at roomtemperature for 2 hours. After completion of the reaction, the reactorwas purged again with nitrogen gas. The 5% Pd/C was filtered off and themethanol was distilled out under reduced pressure. The resultingsolution was cooled to -40° C., to which 250 μl of triethylamine wereadded under a nitrogen gas atmosphere. To the solution so obtained, 5 mlof a methylene chloride solution of 2-N,N-bis(2-chloroethyl)amino!benzoyl chloride (1.1 equivalents), whichhad been prepared right before from 2-N,N-bis(2-chloroethyl)amino!benzoic acid, were added dropwise. Thethus-obtained solution was stirred, as was, for 30 minutes. Methanol wasadded, followed by further stirring for 10 minutes. The solvent wasdistilled out under reduced pressure and the residue was purified bychromatography on a silica gel column (ethyl acetate/IPA/water=5/2/1),whereby 291 mg of white powder were obtained (yield: 61%).

Elemental analysis for C₂₇ H₃₁ N₈ O₂ Cl₃.2H₂ O: Calculated: C, 50.51; H,5.50; N, 17.45 Found: C, 50.17; H, 5.36; N, 16.92

EXAMPLE 17

(Compound No. 15)

1H-2- 4- 3-N,N-bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 3- N,N-bis(2-hydroxyethyl)amino!benzoate

Methyl 3-aminobenzoate (3.8 g; 25 mmol) was reacted with 11 g (250 mmol;10 equivalents) of ethylene oxide in 25 ml of 30% acetic acid, followedby post treatments. The crude product so obtained was purified bychromatography on a silica gel column (eluted with methylenechloride/2-4% methanol), whereby 5.95 g (24.9 mmol) of the titlecompound were obtained as a yellow oil (yield: quantitative).

(Reaction 2)

Methyl 3- N,N-bis(2-chloroethyl)amino!benzoate

Methyl 3- N,N-bis(2-hydroxyethyl)amino!benzoate (3.0 g; 12.5 mmol) wasdissolved in 50 ml of benzene, to which 7.5 ml (103 mmol; 8.3equivalents) of thionyl chloride were added dropwise under ice cooling.The resulting mixture was stirred under heating for 1.5 hours over anoil bath which was controlled at 80° C. The mixture was concentratedunder reduced pressure and ethyl acetate was added to the residue. Theethyl acetate solution was washed twice with a saturated aqueoussolution of sodium hydrogencarbonate and then with a saturated aqueoussolution of sodium chloride. The solution was dried over sodium sulfateand then concentrated under reduced pressure. The resulting concentratewas purified by chromatography on a silica gel column (eluted withn-hexane/ethyl acetate=5/1) and then washed with n-hexane, whereby 2.44g (8.83 mmol) of the title compound were obtained as white crystals(yield: 70.7%).

m.p. 60.5°-61.5° C.

(Reaction 3)

3- N,N-Bis(2-chloroethyl)amino!benzoic acid

Concentrated hydrochloric acid (40 ml) was added to 2.0 g (7.44 mmol) ofmethyl 3- N,N-bis(2-chloroethyl)amino!benzoate, followed by stirringunder heating for 3 hours over an oil bath which was controlled at 90°C. The reaction mixture was diluted with water. The resulting crystalswere collected by filtration and then washed with 50% ethanol, whereby1.95 g (7.44 mmol) of the title compound were obtained as white crystals(yield: quantitative).

m.p. 179°-180° C.

(Reaction 4)

1H-2- 4- 3-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide (0.80 g; 2.0 mmol) was suspended in amixed solvent of 15 ml of DMF and 10 ml of methanol, followed by theaddition of 0.18 ml (2.16 mmol; 1.1 equivalents) of concentratedhydrochloric acid. Using 0.38 g of 10% Pd/C, hydrogenation was conductedunder normal pressure so that the reactant was converted to itscorresponding amino derivative. A solution of half the amino derivativein DMF was stirred under a nitrogen gas atmosphere and ice cooling, towhich 0.30 ml (2.15 mmol; 1.1 equivalents) of triethylamine were added.To the thus-obtained mixture, a solution of 3-N,N-bis(2-chloroethyl)amino!benzoyl chloride, which had been synthesizedfrom 3- N,N-bis(2-chloroethyl)amino!benzoic acid while using thionylchloride, in 5 ml of benzene was added dropwise over 7 minutes. Thetemperature of the resultant mixture was allowed to rise back to roomtemperature, at which the mixture was stirred for 3 hours. The resultingwhite crystals were filtered off and the filtrate was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (ethyl acetate/IPA/water=6/2/1) and then crystallized fromethanol-ethyl ether, whereby 0.39 g (0.64 mmol) of the title compoundwas obtained as pale yellow white crystals (yield: 64.0%).

m.p.>275° C.

IR(KBr)cm⁻¹ : 3257, 1637, 1551, 1350, 1308, 747.

Elemental analysis for C₂₇ H₃₀ N₈ O₂ Cl₂.HCl.1.8H₂ O: Calculated: C,50.80; H, 5.46; N, 17.55; Cl, 16.66 Found: C, 51.09; H, 5.54; N, 17.15;Cl, 16.57

EXAMPLE 18

(Compound No. 13)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!phenoxyacetylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 4-nitrophenoxyacetate

Thionyl chloride (2.3 ml) was added dropwise under ice cooling to asolution of 5.0 g (25 mmol) of 4-nitrophenoxyacetic acid in 250 ml ofmethanol, followed by stirring at room temperature for 1 hour. After thesolvent was distilled out under reduced pressure, the residue wasdissolved in 50 ml of methylene chloride, followed by neutralizationwith an aqueous solution of sodium hydrogencarbonate. The organic layerwas washed with a saturated aqueous solution of sodium chloride and thendried over sodium sulfate. The solvent was thereafter distilled outunder reduced pressure, whereby 5.2 g of pale yellow powder wereobtained (yield: 96%).

IR(KBr)cm⁻¹ : 2446, 1753, 1594, 1340, 1221, 856.

(Reaction 2)

Methyl 4-aminophenoxyacetate

Methyl 4-nitrophenoxyacetate (5.0 g; 24 mmol) was dissolved in 150 ml ofmethanol in a reactor, followed by the addition of 480 mg of 5% Pd/C.The reactor was purged with nitrogen gas. Under a hydrogen gasatmosphere, the resultant mixture was stirred at room temperature for 2hours. After completion of the reaction, the reactor was purged againwith nitrogen gas. The Pd/C was filtered off and the solvent was thendistilled out under reduced pressure, whereby 4.1 g of a brown oil wereobtained (yield: 92%).

(Reaction 3)

Methyl 4- N,N-bis(2-hydroxyethyl)amino!phenoxyacetate

Ethylene oxide (10 g; 227 mmol) was added under ice cooling to asolution of 4.0 g (22 mmol) of methyl 4-aminophenoxyacetate in 22 ml of30% acetic acid. After the resultant mixture was stirred overnight atroom temperature, nitrogen gas was bubbled to eliminate excess ethyleneoxide. Subsequent to neutralization with sodium hydrogencarbonate,sodium chloride was added, followed by extraction with n-butanol. Theextract was dried over magnesium sulfate and the solvent was distilledout. The residue was purified by chromatography on a silica gel column(chloroform/methanol=20/1), whereby 5.29 g of the title compound wereobtained as a colorless oil (yield: 89%).

(Reaction 4)

Methyl 4- N,N-bis(2-chloroethyl)amino!phenoxyacetate

Thionyl chloride (3.17 g; 26.6 mmol) was added dropwise under icecooling to a solution of 2.39 g (8.87 mmol) of methyl 4-N,N-bis(2-hydroxyethyl)amino!phenoxyacetate in 72 ml of1,2-dichloroethane. The thus-obtained mixture was stirred at roomtemperature for 4 hours and then concentrated. The resulting residue waspurified by flush chromatography (chloroform/methanol=200/3), whereby2.0 g of the title compound were obtained as brown crystals (yield:74%).

m.p. 69°-70° C.

IR(KBr)cm⁻¹ : 3449, 2956, 1759, 1516, 1440, 1257, 1220, 1092, 829.

(Reaction 5)

4- N,N-Bis(2-chloroethyl)amino!phenoxyacetic acid

A suspension of 1.99 g (6.50 mmol) of methyl 4-N,N-bis(2-chloroethyl)amino!phenoxyacetate in 60 ml of concentratedhydrochloric acid was heated at 50° C. for 30 minutes. The suspensionwas washed with methylene chloride, neutralized with sodiumhydrogencarbonate, and then extracted with methylene chloride. Theextract was washed with a saturated aqueous solution of sodium chloride,dried over magnesium sulfate and then concentrated, whereby 1.23 g ofthe title compound were obtained as colorless crystals (yield: 65%).

m.p. 112°-113° C.

IR(KBr)cm⁻¹ : 3436, 2968, 1743, 1514, 1433, 1235, 1201, 1099, 817.

(Reaction 6)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!phenoxyacetylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

A solution of 302 mg (0.77 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride in 35 ml of methanol-DMFwas subjected at room temperature to catalytic reduction in the presenceof 10% Pd/C as a catalyst, whereby the corresponding amino derivativewas obtained. The amino derivative was added with triethylamine and alsowith 4- N,N-bis(2-chloroethyl)amino!phenoxyacetyl chloride which hadbeen prepared from 4- N,N-bis(2-chloroethyl)amino!phenoxyacetic acid andoxalyl chloride. The resultant mixture was stirred for 30 minute andthen concentrated. The residue was purified by flush columnchromatography (ethyl acetate/IPA/water=6/2/1), whereby 218 mg of thetitle compound were obtained (yield: 44%).

m.p. 270°-290° C. (dec.).

IR(KBr)cm⁻¹ : 3271, 1687, 1639, 1561, 1511, 1238, 1069, 816, 746.

EXAMPLE 19

(Compound No. 310)

1H-2- 4- 3,5-BisN,N-bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 3,5-diaminobenzoate

Thionyl chloride (3.7 g) was added dropwise under ice cooling to asolution of 5.0 g (33 mmol) of 3,5-diaminobenzoic acid in 250 ml ofmethanol, followed by stirring at room temperature for 2 hours and thenstirring under heating and reflux for additional 6 hours. After thesolvent was distilled out under reduced pressure, the residue wasneutralized with aqueous ammonia and then extracted with methylenechloride. The extract was dried over sodium sulfate and then dried upunder reduced pressure, whereby 3.3 g of white powder were obtained(yield: 60%).

IR(KBr)cm⁻¹ : 3389, 3314, 3219, 1705, 1602, 771.

(Reaction 2)

Methyl 3,5-bis N,N-bis(2-hydroxyethyl)amino!benzoate

Ethylene oxide (15 g; 341 mmol) was added under ice cooling to asolution of 2.8 g (17 mmol) of methyl 3,5-diaminobenzoate in 17 ml of30% acetic acid. After the resultant mixture was stirred overnight atroom temperature, nitrogen gas was bubbled to eliminate excess ethyleneoxide. Subsequent to neutralization of the resultant mixture with sodiumhydrogencarbonate, the mixture was extracted with n-butanol whilesalting it out with sodium chloride. The extract was dried overmagnesium sulfate. After the solvent was distilled out, the residue soobtained was purified by chromatography on a column(methanol/chloroform=1/10), whereby 1.94 g of the title compound wereobtained as colorless crystals.

(Reaction 3)

Methyl 3,5-bis N,N-bis(2-chloroethyl)amino!benzoate

Mixed were 1.94 g (5.67 mmol) of methyl 3,5-bisN,N-bis(2-hydroxyethyl)amino!benzoate and 19 ml of phosphorusoxychloride, followed by heating at 90° C. for 1 hour (the benzoatedissolved in several minutes after the initiation of the heating). Aftercompletion of the reaction, the reaction mixture was concentrated. Theresidue so obtained was carefully added to an ice-cooled aqueoussolution of sodium hydrogencarbonate, followed by extraction with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride, dried over magnesium sulfate and then concentrated. Theconcentrate was purified by flush chromatography(methanol/chloroform=3/200), whereby 1.74 g of the title compound wereobtained as brown crystals.

(Reaction 4)

3,5-Bis N,N-bis(2-chloroethyl)amino!benzoic acid

A suspension of 1.59 g (3.82 mmol) of methyl 3,5-bisN,N-bis(2-chloroethyl)amino!benzoate in 48 ml of concentratedhydrochloric acid was heated at 50° C. for 5 hours. After completion ofthe reaction, the suspension was extracted with methylene chloride. Theextract was washed with an aqueous solution of sodium hydrogencarbonateand then with a saturated aqueous solution of sodium chloride, driedover magnesium sulfate, and was then concentrated. The resultant residuewas purified by flush chromatography (methanol/chloroform=1/20), whereby1.01 g of the title compound were obtained as colorless crystals.

(Reaction 5)

1H-2- 4- 3,5-BisN,N-bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

After purging a reactor with nitrogen gas, a solution of 300 mg (0.766mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride and 0.84 ml of 1Nhydrochloric acid in 30 ml of methanol-DMF was ice-cooled and then addedwith 145 mg of 10% Pd/C. Thereafter, the resultant mixture was stirredunder a hydrogen gas atmosphere at room temperature for 45 minutes.After completion of the reaction, Pd/C was filtered off under a nitrogengas stream. The filtrate was washed with degasified DMF. Thethus-obtained filtrate was thoroughly concentrated. To the concentrate,186 mg (1.84 mmol) of triethylamine and 5.0 ml of 3,5-bisN,N-bis(2-chloroethyl)amino!benzoyl chloride--0.193 M/1,2-dichloroethanesolution; prepared by adding 368 mg (2.9 mmol) of oxalyl chloridedropwise at -20° C. to a solution of 389 mg (0.967 mmol) of 3,5-bisN,N-bis(2-chloroethyl)amino!benzoic acid in 12 ml of 1,2-dichloroethane,stirring the resultant mixture overnight at room temperature,concentrating the mixture to dryness, and then dissolving thethus-obtained oil in 5.0 ml of 1,2-dichloroethane--were added dropwiseat -78° C. under a nitrogen gas atmosphere, followed by stirring for 30minutes. After completion of the reaction, the reaction mixture wasconcentrated and the residue was subjected to flush columnchromatography (ethyl acetate/IPA/water=6/2/1), whereby 76.5 mg of thetitle compound were obtained as an amorphous substance (yield: 13%).

IR(KBr)cm⁻¹ : 3396, 1638, 1591, 1552, 1476, 1409, 1358, 1306, 746.

Elemental analysis for C₃₁ H₃₇ N₉ O₂ Cl₄.HCl.1.5H₂ O: Calculated: C,48.17; H, 5.35; N, 16.31 Found: C, 48.09; H, 5.60; N, 16.02

EXAMPLE 20

(Compound No. 2)

1H-2- 4- 2- 4-N,N-Bis(2-chloroethyl)amino!phenyl!acetylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 4- N,N-bis(2-hydroxyethyl)amino!phenylacetate

Methyl 4-aminophenylacetate (5.5 g; 33 mmol) was reacted with 45 g (341mmol, 10 equivalents) of ethylene oxide in 33 ml of 30% acetic acid,followed by post treatments. The crude product so obtained was purifiedby chromatography on a silica gel column (n-hexane/ethylacetate=1/2→1/4) and washed with n-hexane, whereby 6.07 g (24.0 mmol) ofthe title compound were obtained as white crystals (yield: 72.6%).

(Reaction 2)

Methyl 4- N,N-bis(2-chloroethyl)amino!phenylacetate

Methyl 4- N,N-bis(2-hydroxyethyl)amino!phenylacetate (3.0 g; 11.8 mmol)was dissolved in 8 ml of benzene, followed by the dropwise addition of 3ml (32.2 mmol; 2.7 equivalents) of phosphorus oxychloride under icecooling. The resultant mixture was stirred under heat for 1.5 hours overan oil bath which was controlled at 80° C. The reaction mixture wasadded dropwise to water to hydrolyze any unreacted phosphorusoxychloride. The reaction mixture was then extracted with ethyl acetate.The extract was washed with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, and then concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (n-hexane/ethyl acetate=4/1), whereby 2.97 g (10.2 mmol) of thetitle compound were obtained as a yellow oil (yield: 81.0%).

(Reaction 3)

4- N,N-Bis(2-chloroethyl)amino!phenylacetic acid

Concentrated hydrochloric acid (10 ml) was added to 2.0 g (6.9 mmol) ofmethyl 4- N,N-bis(2-chloroethyl)amino!phenylacetate, followed bystirring under heat for 1 hour over an oil bath controlled at 90° C. Thereaction mixture was diluted with water and was then extracted threetimes with methylene chloride. As the raw material still remained, thereaction product was extracted with a 1N aqueous solution of sodiumhydroxide. The water layer was acidified with hydrochloric acid and thenextracted again with methylene chloride. The extract was dried andconcentrated under reduced pressure. The residue so obtained was washedwith n-hexane, whereby 1.61 g (5.83 mmol) of the title compound wereobtained as white crystals (yield: 84.5%).

m.p. 102.5°-104° C.

(Reaction 4)

1H-2- 4- 2- 4-N,N-Bis(2-chloroethyl)amino!phenylacetylamino!-1-methylpyrrol-2-yl!benimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (0.80 g; 2.0 mmol) wassuspended (practically undissolved) in a mixed solvent of 15 ml of DMFand 10 ml of methanol, followed by the addition of 0.18 ml (2.16 mmol;1.1 equivalents) of concentrated hydrochloric acid. Using 0.38 g of 10%Pd/C as a catalyst, hydrogenation was conducted under normal pressure sothat the reactant was converted to its corresponding amino derivative.Half the amount of the amino derivative was dissolved in DMF. Thesolution so obtained was stirred under a nitrogen gas atmosphere and icecooling, to which 0.30 ml (2.15 mmol; 1.1 equivalents) of triethylaminewas added. A solution of 1.12 mmol of 4-N,N-bis(2-chloroethyl)amino!phenylacetyl chloride in 5 ml of methylenechloride was added dropwise over 7 minutes. The temperature of thethus-obtained mixture was allowed to rise again to room temperature, atwhich the mixture was stirred for 1.5 hours. The resulting whitecrystals were filtered off, followed by concentration under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (ethyl acetate/IPA/water=6/2/1) and then crystallized fromethanol-ethyl ether, whereby 0.33 g (0.53 mmol) of the title compoundwas obtained as pale yellow white amorphous powder (yield: 53.2%).

IR(KBr)cm⁻¹ : 3409, 1637, 1519, 1308

EXAMPLE 21

(Compound No. 6)

1H-2- 4- 3-Methoxy-4-N,N-bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 3-methoxy-4-nitrobenzoate

Thionyl chloride (3.7 g) was added dropwise under ice cooling to asolution of 4.7 g (24 mmol) of 3-methoxy-4-nitrobenzoic acid in 250 mlof methanol. The thus-obtained mixture was stirred at room temperaturefor 2 hours and then stirred under heating and reflux for 3 hours. Afterthe solvent was distilled out under reduced pressure, the residue wasneutralized with aqueous ammonia and then extracted with methylenechloride. The extract was dried over sodium sulfate and then dried upunder reduced pressure, whereby 4.9 g of white powder were obtained(yield: 97%).

IR(KBr)cm⁻¹ : 1732, 1614, 1529, 1306, 1249, 745.

(Reaction 2)

Methyl 3-methoxy-4-aminobenzoate

Methyl 3-methoxy-4-nitrobenzoate (4.8 g; 23 mmol) was dissolved in 150ml of a 2:1 mixed solvent of methanol and tetrahydrofuran, followed byaddition of 480 mg of 5% Pd/C. The resulting mixture was stirred for 2hours under a hydrogen gas atmosphere at room temperature. Aftercompletion of the reaction, the Pd/C was filtered off and the solventwas distilled out under reduced pressure, whereby 3.9 g of whitecrystals were obtained (yield: 54%).

IR(KBr)cm⁻¹ : 3482, 3362, 1680, 1311, 1231, 765

(Reaction 3)

Methyl 3-methoxy-4- N,N-bis(2-hydroxyethyl)amino!benzoate

Ethylene oxide (16.5 ml; 333 mmol) was added dropwise under ice coolingto a solution of 3.9 g (22 mmol) of methyl 3-methoxy-4-aminobenzoate in33 ml of a 30% acetic acid suspension. The thus-obtained was stirred for1 hour and then stirred at room temperature for 2 nights. The mixturewas then stirred for 2 hours while bubbling nitrogen gas therethrough.Sodium hydrogencarbonate was added to the mixture to neutralized thesame. Sodium chloride was then added until saturation, followed byextraction with ethyl acetate. The extract was dried over magnesiumsulfate and the solvent was distilled out under reduced pressure. Theresidue was purified by chromatography on a silica gel column (methylenechloride/ethyl acetate=1:1→0:1), whereby 3.1 g of a pale yellow oil wereobtained (yield: 54%).

IR(KBr)cm⁻¹ : 3421, 2951, 1716, 1268, 1033, 766.

(Reaction 4)

Methyl 3-methoxy-4- N,N-bis(2-chloroethyl)amino!benzoate

Thionyl chloride (0.7 ml; 9.6 mmol) was added to a solution of 1.0 g(3.7 mmol) of methyl 3-methoxy-4- bis(2-hydroxyethyl)amino!benzoate in20 ml of methylene chloride, followed by stirring at room temperaturefor 3 hours. After the solvent was distilled out under reduced pressure,methylene chloride was added again in a small amount and was thendistilled out under reduced pressure. This procedure was repeated twice.The resultant mixture was evaporated to dryness under reduced pressure,whereby 1.0 g of a brown oil was obtained (yield: 88%).

(Reaction 5)

3-Methoxy-4- N,N-bis(2-chloroethyl)amino!benzoic acid

Methyl 3-methoxy-4- bis(2-chloroethyl)amino!benzoate (1.0 g; 3.3 mmol)was added to 20 ml of concentrated hydrochloric acid, followed bystirring for 30 minutes under heating and reflux. The solvent wasdistilled out under reduced pressure, whereby 707 mg of white powderwere obtained (yield: 74%).

IR(KBr)cm⁻ : 3435, 1674, 1600, 1279, 751.

(Reaction 6)

1H-2- 4- 3-Methoxy-4-N,N-bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (300 mg; 0.77 mmol) wasdissolved in 25 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 850 μl of 1N hydrochloric acid and250 mg of 5% Pd/C. The reactor was purged with nitrogen gas. Theresulting mixture was stirred under a hydrogen gas atmosphere at roomtemperature for 2 hours. After completion of the reaction, the reactorwas purged again with nitrogen gas. The Pd/C was filtered off and themethanol was distilled out under reduced pressure. The resultingsolution was cooled to -40° C., to which 250 μl of triethylamine wereadded under a nitrogen gas atmosphere. To the solution so obtained, 5 mlof a methylene chloride solution of 3-methoxy-4-N,N-bis(2-chloroethyl)amino!benzoyl chloride (1.1 equivalents), whichhad been prepared right before, were added dropwise. The thus-obtainedsolution was stirred, as was, for 30 minutes. Methanol was added,followed by further stirring for 10 minutes. The solvent was distilledout under reduced pressure and the residue was purified bychromatography on a silica gel column (ethyl acetate/IPA/water=5/2/1),whereby 241 mg of white powder were obtained (yield: 49%).

IR(KBr)cm⁻¹ : 3422, 2312, 1685, 1541, 1313, 756.

EXAMPLE 22

(Compound No. 3)

1H-2- 4- 3- 4-N,N-Bis(2-chloroethyl)amino!phenyl!propionylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 4- N,N-bis(2-hydroxyethyl)amino!phenylpropionate

Methyl 3-(4-aminophenyl)propionate (4.3 g; 24 mmol) was reacted with 11g (250 mmol, 10 equivalents) of ethylene oxide in 24 ml of 30% aceticacid in a similar manner to Reaction 3 in Example 21. The reactionmixture was worked up. The crude product so obtained was purified bychromatography on a silica gel column (methylene chloride/2-4% methanol)and then crystallized from n-hexane-ethyl ether, whereby 5.04 g (18.9mmol) of the title compound were obtained as white crystals (yield:78.6%).

(Reaction 2)

Methyl 3- 4- N,N-bis(2-chloroethyl)amino!phenyl!propionate

Methyl 3- 4- N,N- bis(2-hydroxyethyl)!amino!phenyl!propionate (2.0 g;7.48 mmol) was dissolved in 5 ml of benzene, followed by the dropwiseaddition of 2 ml (21.5 mmol; 2.9 equivalents) of phosphorus oxychlorideunder ice cooling. The resultant mixture was stirred under heat for 1.5hours over an oil bath which was controlled at 80° C. The reactionmixture was added dropwise to water to hydrolyze any unreactedphosphorus oxychloride. The reaction mixture was then extracted withethyl acetate. The extract was washed with a saturated aqueous solutionof sodium chloride, dried over sodium sulfate, and then concentratedunder reduced pressure. The residue was purified by chromatography on asilica gel column (n-hexane/ethyl acetate=4/1), whereby 1.87 g (6.15mmol) of the title compound were obtained as a yellow oil (yield:82.2%).

(Reaction 3)

3- 4- N,N-Bis(2-chloroethyl)amino!phenyl!propionic acid

Concentrated hydrochloric acid (10 ml) was added to 1.5 g (4.93 mmol) ofmethyl 3- 4- N,N-bis(2-chloroethyl)amino!phenyl!propionate, followed bystirring under heat for 2.5 hours over an oil bath controlled at 90° C.The reaction mixture was diluted with water and was then adjusted toabout pH 2 or so with a 5N aqueous solution of sodium hydroxide. Theresultant crystals were collected by filtration, whereby 1.21 g (4.17mmol) of the title compound were obtained as white crystals (yield:84.6%).

(Reaction 4)

3- 4- N,N-Bis(2-chloroethyl)amino!phenyl!propionyl chloride

3- 4- N,N-Bis(2-chloroethyl)amino!phenyl!propionic acid (0.24 g; 0.83mmol) was dissolved in 5 ml of 1,2-dichloroethane, followed by thedropwise addition of 0.22 ml (2.58 mmol; 3.1 equivalents) of oxalylchloride (with ice-cooling from an intermediary time point due toviolent exotherm). After completion of the dropwise addition, thetemperature of the resultant mixture was allowed to rise again to roomtemperature, at which the mixture was stirred for 3 hours and thenallowed to stand overnight. The mixture was thereafter concentratedunder reduced pressure, whereby the title compound was obtained in acrude form. The crude compound was provided for use in the next reactionwithout purification.

(Reaction 5)

1H-2- 4- 3- 4-N,N-Bis(2-chloroethyl)amino!phenyl!propionylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (0.30 g; 0.77 mmol) wassuspended in a mixed solvent of 10 ml of DMF and 6.5 ml of methanol,followed by the addition of 65 μl (0.78 mmol; 1.0 equivalent) ofconcentrated hydrochloric acid. Using 0.12 g of 10% Pd/C as a catalyst,hydrogenation was conducted under normal pressure so that the reactantwas converted to its corresponding amino derivative. The aminoderivative was dissolved in DMF. The solution so obtained was stirredunder a nitrogen gas atmosphere and ice cooling, to which 0.21 ml (1.5mmol; 1.9 equivalents) of triethylamine was added. A solution of 0.83mmol of 3- 4- N,N-bis(2-chloroethyl)amino!phenyl!propionyl chloride in 2ml of methylene chloride was added dropwise over 7 minutes. Thetemperature of the thus-obtained mixture was allowed to rise again toroom temperature, at which the mixture was stirred for 4.5 hours. Theresulting white crystals were filtered off, followed by concentrationunder reduced pressure. The residue was purified by chromatography on asilica gel column (ethyl acetate/IPA/water=6/2/1) and then crystallizedfrom ethanol-ethyl ether, whereby 0.25 g (0.37 mmol) of the titlecompound was obtained as a pale yellow white amorphous substance (yield:47.6%).

m.p.: No distinct melting point was observed.

IR(KBr)cm⁻¹ : 3267, 1638, 1546, 1519, 1350, 1308, 812, 747.

Elemental analysis for C₂₉ H₃₄ N₈ O₂ Cl₂.HCl.2H₂ O: Calculated: C,51.98; H, 5.87; N, 16.72; Cl, 15.87 Found: C, 51.68; H, 5.83; N, 16.45Cl, 16.26

EXAMPLE 23

(Compound No. 260)

1H-2- 4- 4-N,N-Bis(2-bromoethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Ethyl 4- N,N-bis(2-bromoethyl)amino!benzoate

Phosphorus tribromide (1.1 ml; 11.3 mmol) was added under ice-cooling toa solution of 2.0 g (7.9 mmol) of ethyl 4-N,N-bis(2-hydroxyethyl)amino!benzoate in 50 ml of methylene chloride.The resulting mixture was stirred, as was, for 2 hours, followed byfurther stirring at room temperature for 12 hours. After the solvent wasdistilled out under reduced pressure, the residue was dissolved inethanol and the insoluble matter was eliminated. The product waspurified by chromatography on a silica gel column (ethylacetate/n-hexane=3/1), whereby 1.0 g of white powder was obtained(yield: 34%).

(Reaction 2)

4- N,N-Bis(2-bromoethyl)amino!benzoic acid

Ethyl 4- N,N-bis(2-bromoethyl)amino!benzoate (1.0 g; 2.6 mmol) was addedto 10 ml of a 47% aqueous solution of hydrobromic acid, followed bystirring for 30 minutes under heating and reflux. The solvent wasdistilled out under reduced pressure, whereby 650 mg of white powderwere obtained (yield: 70%).

(Reaction 3)

1H-2- 4- 4-N,N-Bis(2-bromoethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide (200 mg; 0.51 mmol) was dissolved in 20ml of a 1:1 mixed solvent of DMF and methanol in a reactor, followed bythe addition of 200 mg of 5% Pd/C and 0.7 ml of 1N hydrochloric acid.The reactor was purged with nitrogen gas. The resulting mixture wasstirred under a hydrogen gas atmosphere at room temperature for 2 hours.After completion of the reaction, the reactor was purged again withnitrogen gas. The 5% Pd/C was filtered off and the methanol wasdistilled out under reduced pressure. The resulting solution was cooledto 0° C., to which 0.17 ml of triethylamine and a solution of 4-N,N-bis(2-bromoethyl)amino!benzoyl chloride (1.1 equivalents), which hadbeen prepared right before, in 5 ml of DMF were added dropwise under anitrogen gas atmosphere. The resultant mixture was stirred, as was, for30 minutes. Methanol was added, followed by further stirring for 5minutes. The solvent was distilled out under reduced pressure and theresidue was purified by chromatography on a silica gel column (ethylacetate/IPA/water=5/2/1), whereby 193 mg of white powder were obtained(yield: 55%).

m.p.>270° C.

IR(KBr)cm⁻¹ : 3292, 2367, 1690, 1606, 1543, 1350, 1204.

Elemental analysis for C₂₇ H₃₁ N₈ O₂ Cl₁ Br₂.5H₂ O: Calculated: C,41.17; H, 4.43; N, 14.00 Found: C, 41.32; H, 4.43;N, 14.28

EXAMPLE 24

(Compound No. 332)

1H-2-(4-Benzoylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-aminoethyl)!carboxamide hydrochloride

(Reaction 1)

1H-2-(4-Benzoylamino-1-methylpyrrol-2-yl)benzimidazole-5- N-2-(t-butoxycarbonylamino)ethyl!!-carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-2-(t-butoxycarbonylamino)ethyl!!carboxamide (0.11 g; 0.26 mmol) wassuspended in a mixed solvent of 3 ml of DMF and 2 ml of methanol. Using0.10 g of 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure so that the reactant was converted to its correspondingamino derivative. A DMF solution of the amino derivative was stirredunder a nitrogen gas atmosphere and ice cooling, to which 45 μl (0.32mmol; 1.2 equivalents) of triethylamine was added, followed by thedropwise addition of 36 μl (0.31 mmol; 1.2 equivalents) of benzoylchloride. The resultant mixture was stirred, as was, for 4 hours and wasthen allowed to stand overnight. The mixture was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (chloroform/8% methanol).Relevant fractions wereconcentrated, whereby 103 mg (0.20 mmol) of the title compound wereobtained as amorphous powder (yield: 82.0%).

(Reaction 2)

1H-2-(4-Benzoylamino-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-aminoethyl)!carboxamide hydrochloride

1H-2-(4-Benzoylamino-1-methylpyrrol-2-yl)benzimidazole-5- N-2-(t-butoxycarbonylamino)ethyl!!carboxamide (0.10 g; 0.20 mmol) wasdissolved in 2 ml of trifluoroacetic acid, followed by stirring at roomtemperature for 1 hour. The resultant mixture was concentrated underreduced pressure. After evaporated with toluene, 2 ml of 4N HCl/dioxanewas added. The thus-obtained mixture was stirred for 1 hour, followed byconcentration under reduced pressure. The residue was crystallized fromethyl ether, whereby 84 mg (0.18 mmol) of the title compound wereobtained as pale yellow white crystals (yield: 88.8%).

m.p. 252°-260° C.

IR(KBr)cm⁻¹ : 3400, 3044, 1647, 1560, 1395, 1321, 823, 705.

Elemental analysis for C₂₂ H₂₂ N₆ O₂.2HCl.1.5H₂ O: Calculated: C, 52.60;H, 5.42; N, 16.73 Cl, 14.11 Found: C, 52.73; H, 5.47; N, 16.46; Cl,13.95

EXAMPLE 25

(Compound No. 129)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-aminoethyl)!carboxamide hydrochloride

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-2-(t-butoxycarbonylamino)ethyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.10g; 0.35 mmol) was dissolved in 5 ml of DMF, followed by the addition of0.07 g (0.43 mmol; 1.2 equivalents) of CDI. The resultant mixture wasstirred under a nitrogen gas atmosphere at room temperature for 2.5hours and was then ice-cooled, to which a solution of 0.07 g (0.44 mmol;1.2 equivalents) of N-t-butoxycarbonyl-1,2-ethanediamine in 2 ml of DMFwas added. The temperature of the thus-obtained mixture was allowed torise again to room temperature, at which the mixture was stirred for 4hours and then allowed to stand overnight. The mixture was thenconcentrated under reduced pressure. The residue was washed withmethanol, whereby 0.11 g (0.26 mmol) of the title compound was obtainedas yellow crystals (yield: 73.3%).

(Reaction 2)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N- 2-(t-butoxycarbonylamino)ethyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-2-(t-butoxycarbonylamino)ethyl!!carboxamide (0.11 g; 0.26 mmol) wassuspended in a mixed solvent of 3 ml of DMF and 2 ml of methanol. Using0.10 g of 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure so that the reactant was converted to its correspondingamino derivative. A DMF solution of the amino derivative was stirredunder a nitrogen gas atmosphere and ice cooling, to which 0.45 μl (0.32mmol; 1.2 equivalents) of triethylamine was added. A solution of 4-N,N-bis(2-chloroethyl)amino!benzoyl chloride, which had been synthesizedfrom 0.09 g (0.34 mmol) of 4- N,N-bis(2-chloroethyl)amino!benzoic acid,in 2 ml of benzene was added dropwise. The temperature of thethus-obtained mixture was allowed to rise again to room temperature, atwhich the mixture was stirred for 4 hours and was then allowed to standovernight. The mixture was then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column(chloroform/5% methanol). Relevant fractions were concentrated, whereby133 mg (0.21 mmol) of the title compound were obtained as amorphouspowder (yield: 81.0%).

(Reaction 3)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-aminoethyl)!carboxamide hydrochloride

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N- 2-(t-butoxycarbonylamino)ethyl!!carboxamide (0.13 g; 0.20 mmol) wasdissolved in 2 ml of trifluoroacetic acid, followed by stirring at roomtemperature for 30 minutes. The resultant mixture was concentrated underreduced pressure. After evaporated with toluene, 4N hydrochloric acid indioxane was added, followed by concentration. This procedure wasrepeated three times. The residue was crystallized from ethanol, whereby98 mg (0.16 mmol) of the title compound were obtained as pale yellowwhite crystals (yield: 79.6%).

m.p.>275° C.

IR(KBr)cm⁻¹ : 3423, 2959, 1605, 1560, 1389, 1059, 828.

Elemental analysis for C₂₆ H₂₉ N₇ O₂ Cl₂.2HCl.2H₂ O: Calculated: C,47.94; H, 5.42; N, 15.05 Cl, 21.77 Found: C, 48.16; H, 5.34; N, 14.75;Cl, 21.43

EXAMPLE 26

(Compound No. 223)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(3-picolyl)!carboxamide hydrochloride

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(3-picolyl)!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.20g; 0.70 mmol) was dissolved in 5 ml of DMF, followed by the addition of0.17 g (1.05 mmol; 1.5 equivalents) of CDI. The resultant mixture wasstirred under a nitrogen gas atmosphere at room temperature for 1.5hours and was then ice-cooled, to which 0.12 ml (1.18 mmol; 1.7equivalents) of 3-picolylamine was added. The temperature of thethus-obtained mixture was allowed to rise again to room temperature, atwhich the mixture was stirred for 4 hours and then allowed to standovernight. The mixture was then concentrated under reduced pressure. Theresidue was washed with methanol, whereby 0.25 g (0.66 mmol) of thetitle compound was obtained as yellow crystals (yield: 93.8%).

(Reaction 2)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(3-picolyl)!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-N-(3-picolyl)!carboxamide (0.24 g; 0.64 mmol) was suspended in a mixedsolvent of 8 ml of DMF and 5 ml of methanol, followed by the addition of2 equivalents of concentrated hydrochloric acid. Using 0.09 g of 10%Pd/C as a catalyst, hydrogenation was conducted under normal pressure sothat the reactant was converted to its corresponding amino derivative. ADMF solution of the amino derivative was stirred under a nitrogen gasatmosphere and ice cooling, to which 0.2 ml (1.43 mmol; 2.2 equivalents)of triethylamine was added. A solution of 4-N,N-bis(2-chloroethyl)amino!benzoyl chloride, which had been synthesizedfrom 0.18 g (0.69 mmol) of 4- N,N-bis(2-chloroethyl)amino!benzoic acid,in 5 ml of benzene was added dropwise. The temperature of thethus-obtained mixture was allowed to rise again to room temperature, atwhich the mixture was stirred for 4 hours and was then allowed to standovernight. The mixture was then concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column(chloroform/10% methanol). Relevant fractions were suspended in waterand the resulting precipitate was collected by filtration, whereby 0.12g (0.20 mmol) of the title compound was obtained as white crystals(yield: 31.2%). Of the reaction product, 52 mg (0.078 mmol) weresuspended in 2 ml of ethanol, to which 4N hydrochloric acid in dioxanewas added. The resulting mixture was concentrated to obtain crystals.The crystals were washed with ethyl ether, so that the reaction productwas converted to its hydrochloride.

m.p.>275° C.

IR(KBr)cm⁻¹ : 3369, 1655, 1604, 1546, 1277.

Elemental analysis for C₃₀ H₂₉ N₇ O₂ Cl₂.2HCl.2.5H₂ O: Calculated: C,50.86; H, 5.12; N, 13.84 Cl, 20.02 Found: C, 50.67; H, 4.86; N, 13.68;Cl, 20.34

EXAMPLE 27

(Compound No. 247)

3- 1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!-benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-carboxamido!methyl!-1-methylpyridiniumchloride

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N-(3-picolyl)!carboxamide (84 mg; 0.13 mmol) was dissolved in 2 ml ofDMF, followed by the addition of 40 μl (0.642 mmol; 5.1 equivalents) ofmethyl iodide. The resulting mixture was stirred at room temperature for6 hours and was then allowed to stand overnight. The thus-obtainedmixture was concentrated under reduced pressure and the residue wassubjected to chromatography on an ion-exchange column ("DOWEX"1×8,200-400 mesh, Cl⁻ type). Relevant fractions were combined andconcentrated. The residue was crystallized from ethyl ether and thenwashed with chloroform, whereby 46 mg (0.072 mmol) of the title compoundwere obtained as white crystals (yield: 56.5%).

m.p. 189°-193° C. (dec.).

IR(KBr)cm⁻¹ : 3420, 1637, 1605, 1541.

Elemental analysis for C₃₁ H₃₂ N₇ O₂ Cl₃.0.25CHCl₃.2H₂ O: Calculated: C,53.10; H, 5.17; N, 13.87 Cl, 18.81 Found: C, 52.96; H, 5.01; N, 13.50;Cl, 18.53

EXAMPLE 28

(Compound No. 16)

1H-2- 4-(6-Bromohexylamino)-1-methylpyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2- 1-methyl-4-nitropyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (200 mg; 0.51 mmol) wasdissolved in 12 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 200 mg of 5% Pd/C and 0.7 ml of 1Nhydrochloric acid. The reactor was purged with nitrogen gas. Theresultant mixture was stirred under a hydrogen gas atmosphere at roomtemperature for 2 hours. After completion of the reaction, the reactorwas purged again with nitrogen gas. The 5% Pd/C was filtered off and themethanol was distilled out under reduced pressure. The resultingsolution was cooled to 0° C., to which 0.17 ml of triethylamine and 1.1equivalents of 6-bromohexanoic chloride were added under a nitrogen gasatmosphere. The thus-obtained mixture was stirred, as was, for 30minutes. Methanol was added, followed by further stirring for 5 minutes.After the solvent was distilled out under reduced pressure, the residuewas purified by chromatography on a silica gel column (ethylacetate/IPA/water=5/2/1), whereby 200 mg of white powder were obtained(yield: 73%).

IR(KBr)cm⁻¹ : 3272, 2362, 1690, 1637, 1542, 1311, 958.

EXAMPLE 29

(Compound No. 1001)

1H-2- 1-Methyl-4-(2-guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

(Reaction 1)

N,N-Bis(2-chloroethyl)-1,4-phenylenediamine hydrochloride

4-Nitro- N,N-bis(2-chloroethyl)!aniline (5.0 g; 19.0 mmol) was dissolvedin a mixed solvent of 50 ml of ethyl acetate and 25 ml of methanol,followed by the addition of 5.0 ml of 4N hydrochloric acid. Using 10%Pd/C, the reactant was subjected to hydrogenation under normal pressureat room temperature. The Pd/C was filtered off and the solvent wasdistilled out. The residue was crystallized from ethanol-ethyl ether,whereby 4.1 g (15.2 mmol) of the title compound was obtained (yield:80%).

m.p. 230°-233° C.

(Reaction 2)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.3g; 1.05 mmol) was dissolved in 6 ml of DMF, to which a solution of 0.3 g(1.1 mmol; 1.05 equivalents) ofN,N-bis(2-chloroethyl)-1,4-phenylenediamine hydrochloride and 0.15 ml(1.82 mmol; 3.1 equivalents) of triethylamine in 8 ml of DMF was addeddropwise. Added next was 0.16 g (1.18 mmol; 1.1 equivalents) of HOBt.The resulting mixture was ice-cooled under a nitrogen gas atmosphere,followed by the addition of 0.24 g (1.16 mmol; 1.1 equivalents) of DCC.The temperature of the resulting mixture was allowed to rise again toroom temperature, at which the mixture was stirred for 3 hours and wasthen allowed to stand overnight. The resulting solid was filtered offand the filtrate was concentrated under reduced pressure. The residuewas purified by chromatography on a silica gel column (methylenechloride/2% methanol). The reaction product was washed with methanol,whereby 0.38 g (0.76 mmol) of the title compound was obtained as yellowcrystals (yield: 72.2%).

m.p. 144°-148° C.

(Reaction 3)

1H-2- 1-Methyl-4-(2-guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (0.30 g; 0.60 mmol) wasdissolved in a mixed solvent of 3 ml of DMF and 3 ml of methanol. Using0.12 g of Pd/C as a catalyst, the reactant was hydrogenated under normalpressure so that it was converted to the corresponding amino derivative.A DMF solution of the amino derivative was stirred under a nitrogen gasstream and ice-cooling, to which 0.17 ml (1.22 mmol; 2.0 equivalents) oftriethylamine and 0.37 g (1.79 mmol; 3.0 equivalents) of DCC weresuccessively added. The thus-obtained mixture was stirred, as was, for 1hour and was then allowed to stand overnight. The mixture wasconcentrated under reduced pressure and the residue was purified bychromatography on a silica gel column (methylene chloride/12% methanol;repeated twice). From IPA, 78 mg (0.13 mmol) of the title compound wereobtained as light yellow powder (yield: 21.5%).

IR(KBr)cm⁻¹ : 3390, 2925, 1655, 1518, 1458

EXAMPLE 30

(Compound No. 1054)

1H-2- 4-(2-Guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N-4- N,N-bis(2-acetoxyethyl)amino!phenyl!!carboxamide hydrochloride

(Reaction 1)

4-Nitro- N,N-bis(2-acetoxyethyl)!aniline

4-Nitro- N,N-bis(2-hydroxyethyl)!aniline (1.0 g; 4.42 mmol) wasdissolved in 20 ml of pyridine, followed by the addition of 0.80 ml(11.3 mmol; 2.5 equivalents) of acetyl chloride under ice-cooling. Thetemperature of the resulting mixture was allowed to rise again to roomtemperature, at which the mixture was stirred for 2 hours. The mixturewas concentrated under reduced pressure. The residue was added with 0.4N hydrochloric acid and reacted with ethyl acetate. This extraction wasrepeated twice. The extract was washed with an aqueous solution ofhydrochloric acid, dried over sodium sulfate, and then concentrated. Theresidue was washed with ethyl ether/methanol, whereby 1.03 g (3.32 mmol)of the title compound were obtained as yellow white crystals (yield:75.1%).

(Reaction 2)

4- N,N-Bis(2-acetoxyethyl)amino!aniline hydrochloride

4-Nitro- N,N-Bis(2-acetoxyethyl)!aniline (0.30 g; 0.97 mmol) wasdissolved in a mixed solvent of 5 ml of methanol and 3 ml of ethylacetate. Using 10% Pd/C as a catalyst, hydrogenation was conducted undernormal pressure. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was dissolved indioxane, followed by the addition of 4N hydrochloric acid/dioxane. Thethus-obtained mixture was concentrated. The residue was crystallizedfrom ethyl ether/n-hexane/acetone, whereby 0.36 g (1.12 mmol) of thetitle compound was obtained as white crystals (yield: quantitative).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-acetoxyethyl)!amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.25g; 0.88 mmol) was dissolved in 4 ml of DMF, followed by the addition of0.13 g (0.96 mmol; 1.1 equivalents) of HOBt. Further, a solution of 0.34g (1.1 mmol; 1.2 equivalents) of 4- N,N-bis(2-acetoxyethyl)amino!anilinehydrochloride and 0.15 ml (1.82 mmol; 2 equivalents) of triethylamine in6 ml of DMF was added dropwise. The thus-obtained mixture was ice-cooledunder a nitrogen gas atmosphere, to which 0.20 g (0.97 mmol; 1.1equivalents) of DCC was added. The temperature of the resulting mixturewas allowed to rise again to room temperature, at which the mixture wasstirred for 6 hours and was then allowed to stand overnight. Theresulting solid was filtered off and the filtrate was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (eluted with chloroform/2-4% methanol). The reaction productwas then washed with methanol, whereby 0.28 g (0.51 mmol) of the titlecompound was obtained as yellow crystals (yield: 58.0%).

(Reaction 4)

1H-2- 4-(2-guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N-4- N,N-bis(2-acetoxy-ethyl!amino!phenyl!!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazol5- N- 4-N,N-bis(2-acetoxyethyl)amino!phenyl!!carboxamide (0.27 g; 0.49 mmol) wasdissolved in a mixed solvent of 2 ml of DMF and 2 ml of methanol,followed by the addition of 0.12 ml of 4N hydrochloric acid. Using 0.12g of Pd/C as a catalyst, the reactant was hydrogenated under normalpressure so that it was converted to the corresponding amino derivative.A DMF solution of the amino derivative was stirred under a nitrogen gasstream and ice-cooling, to which 70 μl (0.50 mmol; 1.0 equivalent) oftriethylamine, 0.23 g (1.45 mmol; 3.0 equivalents) of 2-guanidineacetate hydrochloride and 0.23 g (1.50 mmol; 3.0 equivalents) of DCCwere successively added. The thus-obtained mixture was stirred, as was,for 2 hours and then allowed to stand overnight. The mixture wasconcentrated under reduced pressure and the residue was purified bychromatography on a silica gel column (the first chromatography:chloroform/16-20% methanol; the second chromatography: ethylacetate/IPA/water=7/2/1→5/2/1). The reaction product was washed withethyl acetate, whereby 0.12 g (0.18 mmol) of the title compound wasobtained as a white amorphous substance (yield: 37.4%).

m.p.: No distinct melting point was observed.

IR(KBr)cm⁻¹ : 3385, 3178, 1735, 1655, 1520, 1231.

EXAMPLE 31

(Compound No. 1003)

1H-2- 4-(2-Guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N-2- 4- N,N-bis(2-chloroethyl)amino!phenyl!ethyl!!carboxamidehydrochloride

(Reaction 1)

2- 4- N,N-Bis(2-chloroethyl)amino!phenyl!ethylamine

3- 4- N,N-Bis(2-chloroethyl)amino!phenyl!propionic acid (0.20 g; 0.69mmol) was suspended in 1 ml of acetone and the resulting mixture wasstirred under a nitrogen gas atmosphere and ice-cooling. Triethylamine(115 μl; 0.82 mmol; 1.2 equivalents) and ethyl chloroformate (79 μl;0.82 mmol; 1.2 equivalents) were added successively. Fifteen minuteslater, a solution of 90 mg (1.38 mmol; 2.0 equivalents) of sodium azidein 1 ml of water was added dropwise. The resulting mixture was stirred,as was, for 30 minutes, to which ice was added to terminate thereaction. The thus-obtained mixture was extracted three times with 15 mlportions of benzene. The benzene layers were combined, dried over sodiumsulfate and then heated under reflux for 1 hour. The reaction mixturewas concentrated under reduced pressure. The residue was added with 7.5ml of 8N hydrochloric acid, followed by heating for 15 minutes at 100°C. The resulting mixture was concentrated under reduced pressure and theresidue was diluted with water. The thus-obtained mixture was adjustedto pH 12 with concentrated aqueous ammonia, followed by extraction withethyl acetate. The extract was dried and concentrated, whereby 0.15 g ofthe title compound was obtained as a brown oil. This reaction productwas provided for use in the next reaction without purification.

(Reaction 2)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2- 4-N,N-bis(2-chloroethyl)amino!phenyl!ethyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.1g; 0.35 mmol) was dissolved in 3 ml of DMF, followed by the addition of68 mg (0.42 mmol; 1.2 equivalents) of CDI. The resulting mixture wasstirred for 1 hour under a nitrogen gas stream at room temperature. Thethus-obtained mixture was ice-cooled, to which a solution of 0.15 g (1.1mmol; 1.05 equivalents: crude) of 2- 4-N,N-bis(2-chloroethyl)amino!phenyl!ethylamine in 2 ml of DMF was addeddropwise. The ice bath was removed. The mixture was stirred for 7 hoursand was then allowed to stand overnight. The thus-obtained mixture wasconcentrated under reduced pressure and methanol was added to theresidue. The precipitated crystals were collected by filtration, whereby0.14 g (0.26 mmol) of the title compound was obtained as light yellowcrystals (yield: 75.6%).

(Reaction 3)

1H-2- 4-(2-guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N-2- 4- N,N-bis(2-chloro-ethyl)amino!phenyl!ethyl!!carboxamidehydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2- 4-N,N-bis(2-chloroethyl)amino!phenyl!ethyl!!carboxamide (0.30 g; 0.57mmol) was dissolved in a mixed solvent of 5 ml of DMF and 5 ml ofmethanol, followed by the addition of 0.6 ml of 1N hydrochloric acid.Using 0.15 g of 10% Pd/C as a catalyst, the reactant was hydrogenatedunder normal pressure so that it was converted to the correspondingamino derivative. A DMF solution of the amino derivative was stirredunder a nitrogen gas stream and ice-cooling, to which 108 μl (0.78 mmol;1.4 equivalents) of triethylamine, 0.26 g (1.7 mmol; 3.0 equivalents) of2-guanidine acetate hydrochloride and 0.36 g (1.7 mmol; 3.0 equivalents)of DCC were successively added. The thus-obtained mixture was stirred,as was, for 1 hour and then allowed to stand overnight. The resultingcrystals were filtered off and the residue was purified bychromatography on a silica gel column (the first chromatography: ethylacetate/IPA/water=7/2/1; the second chromatography: chloroform-12%methanol; the third chromatography: ethyl acetate/IPA/water=7/2/1). Thereaction product was crystallized from ethyl ether, whereby 67 mg (0.11mmol) of the title compound were obtained as white crystals (yield:18.5%).

m.p. 175°-185° C. (dec.).

EXAMPLE 32

(Compound No. 1004)

1H-2- 4-(2-Guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N-3- 4- N,N-bis(2-chloroethyl)amino!phenyl!propyl!!carboxamidehydrochloride

(Reaction 1)

3- 4- N,N-Bis(2-chloroethyl)amino!phenyl!propylamine

Chlorambucil (0.30 g; 0.99 mmol) was suspended in 2 ml of acetone. Theresultant mixture was stirred under a nitrogen gas atmosphere andice-cooling, to which 0.17 ml (1.22 mmol; 1.2 equivalents) oftriethylamine and 0.11 ml (1.22 mmol; 1.2 equivalents) of ethylchloroformate were added successively. Twenty minutes later, a solutionof 0.13 g (2.0 mmol; 2.0 equivalents) of sodium azide in 2 ml of waterwas added dropwise. The resulting mixture was stirred, as was, for 1hour, to which ice was added to terminate the reaction. Thethus-obtained mixture was extracted three times with 20 ml portions ofbenzene. The benzene layers were combined, dried over sodium sulfate andthen heated under reflux for 1 hour. The reaction mixture wasconcentrated under reduced pressure. The residue was added with 9 ml of8N hydrochloric acid, followed by heating for 15 minutes at 100° C. Theresulting mixture was concentrated under reduced pressure and theresidue was diluted with water. The thus-obtained mixture was adjustedto pH 12 with concentrated aqueous ammonia, followed by extraction withethyl acetate. The extract was dried and concentrated, whereby 0.21 g ofthe title compound was obtained as a crude yellow oil of high viscosity.This reaction product was provided for use in the next reaction withoutpurification.

(Reaction 2)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3- 4-N,N-bis(2-chloroethyl)amino!phenyl!propyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.17g; 0.59 mmol) was dissolved in 5 ml of DMF, followed by the addition of0.12 g (0.74 mmol; 1.2 equivalents) of CDI. The resulting mixture wasstirred for 1 hour under a nitrogen gas atmosphere at room temperature.The thus-obtained mixture was ice-cooled, to which a solution of 0.24 g(crude) of 3- 4- N,N-bis(2-chloroethyl)amino!phenyl!propylamine in 2 mlof DMF was added dropwise. The ice bath was removed. The mixture wasstirred for 3 hours and was then allowed to stand overnight. Thethus-obtained mixture was concentrated under reduced pressure andmethanol was added to the residue. The precipitated crystals werecollected by filtration, whereby 0.17 g (0.31 mmol) of the titlecompound was obtained as light yellow crystals (yield: 53.0%).

m.p. 164°-168° C.

(Reaction 3)

1H-2- 4-(2-Guanidinoacetylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N-3- 4- N,N-bis(2-chloroethyl)amino!phenyl!propyl!!carboxamidehydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3- 4-N,N-bis(2-chloroethyl)amino!phenyl!propyl!!carboxamide (0.26 g; 0.48mmol) was dissolved in a mixed solvent of 3 ml of DMF and 3 ml ofmethanol, followed by the addition of 0.12 ml of 4N hydrochloric acid.Using 0.11 g of 10% Pd/C as a catalyst, the reactant was hydrogenatedunder normal pressure so that it was converted to the correspondingamino derivative. A DMF solution of the amino derivative was stirredunder a nitrogen gas stream and ice-cooling, to which 67 μl (0.48 mmol;1.0 equivalent) of triethylamine, 0.22 g (1.43 mmol; 3.0 equivalents) of2-guanidinoacetic acid hydrochloride and 0.30 g (1.45 mmol; 3.0equivalents) of DCC were successively added. The thus-obtained mixturewas stirred, as was, for 6 hours and then allowed to stand overnight.The resulting crystals were filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (ethyl acetate/IPA/water=7/2/1;performed twice). The reaction product was crystallized from ethylether, whereby 91 mg (0.14 mmol) of the title compound were obtained aswhite crystals (yield: 29.2%).

m.p. 168°-173° C.

Elemental analysis for C₂₉ H₃₅ N₉ O₂ Cl₂.2HCl: Calculated: C, 50.81; H,5.44; N, 18.39, Cl, 20.69 Found: C, 50.90, H, 5.80; N, 18.05, Cl,: 21.06

EXAMPLE 33

(Compound No. 2001)

1H-2- 4- 4-N,N-Bis(2-chloroethyl)amino!benzoylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N- 4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (0.18 g; 0.36 mmol) wassuspended in a mixed solvent of 10 ml of DMF and 8 ml of methanol,followed by the addition of 1 equivalent of concentrated hydrochloricacid. Using 0.07 g of 10% Pd/C as a catalyst, the reactant washydrogenated under normal pressure so that it was converted to thecorresponding amino derivative. A DMF solution of the amino derivativewas stirred under a nitrogen gas atmosphere and ice-cooling, to which0.11 ml (0.79 mmol; 2.2 equivalents) of triethylamine was added. Furtheradded dropwise was a solution of 4- N,N-bis(2-chloroethyl)amino!benzoylchloride, which had been synthesized from 0.11 g (0.42 mmol) of 4-N,N-bis-(2-chloroethyl)amino!benzoic acid, in 3 ml of benzene. Thetemperature of the resulting mixture was allowed to rise back to roomtemperature, at which the mixture was stirred for 5 hours and thenallowed to stand overnight. The thus-obtained mixture was concentratedunder reduced pressure and the residue was purified by chromatography ona silica gel column (chloroform/2-4% methanol). The reaction product wascrystallized from ethanol/ethyl ether, whereby 73 mg (0.10 mmol) of thetitle compound were obtained as white crystals (yield: 28.3%).

m.p. 168°-174° C.

IR(KBr)cm⁻¹ : 3414, 1655, 1637, 1606, 1517, 1278.

Elemental analysis for C₃₄ H₃₅ N₇ O₂ Cl₄.1.5H₂ O: Calculated: C, 55.00;H, 5.16; N, 13.20; Cl, 19.10 Found: C, 54.79; H, 4.89; N, 12.96; Cl,18.73

EXAMPLE 34

(Compound No. 342)

1H-2- 1-Methyl-4- 4-N,N-bis(2-chloroethyl)amino!benzoylamino!imidazol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

2-Formyl-1-methylimidazole

To a solution of 0.5 g (6.1 mmol) of 1-methylimidazole in 15 ml of THF(anhydrous), 4.6 ml of a 1.6M n-hexane solution of n-butyllithium (7.4mmol; 1.2 equivalents) were added dropwise under a nitrogen gasatmosphere, ice-cooling and stirring. The temperature of the resultingmixture was allowed to rise back to room temperature. 1.5 Hours later,the mixture was ice-cooled again, to which 1.4 ml (18.1 mmol; 3.0equivalents) of DMF were added dropwise. The thus-obtained mixture wasallowed to stand overnight as was. The resulting white solid wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was dissolved in ethyl acetate. The solution so obtained waswashed with water, dried over sodium sulfate and then concentrated. Theresidue was purified by chromatography on a silica gel column(n-hexane/ethyl acetate=3/1), whereby 0.31 g (2.82 mmol) of the titlecompound was obtained as a yellow oil (yield: 46.2%).

(Reaction 2)

2-Formyl-1-methyl-4-nitroimidazole

Fuming nitric acid (3 ml) was cooled to -10° C., to which 3 ml ofconcentrated sulfuric acid were added dropwise. The resulting mixturewas added dropwise at an internal temperature of -10° C. or lower to 0.5g (4.54 mmol) of 2-formyl-1-methylimidazole. The temperature of thethus-obtained was naturally allowed to rise to room temperature, atwhich the mixture was allowed to stand overnight. The reaction mixturewas poured into ice, followed by neutralization with sodium carbonate.The resultant mixture was extracted twice with methylene chloride. Theorganic layers were washed with a saturated aqueous solution of sodiumhydrogencarbonate, dried over sodium sulfate and then concentrated. Theresidue was crystallized from ethyl ether/ethanol, whereby 0.21 g (1.35mmol) of the title compound was obtained as cream-colored crystals(yield: 29.8%).

m.p. 140°-142° C.

(Reaction 3)

1H-2-(1-Methyl-4-nitroimidazol-2-yl)benzimidazole-5-carboxylic acid

Suspended in 75 ml of nitrobenzene were 1.48 g (9.54 mmol) of2-formyl-1-methyl-4-nitroimidazole and 1.45 g (9.53 mmol; 1.0equivalent) of 3,4-diaminobenzoic acid. The resulting suspension wasstirred for 27 hours under heat over an oil bath which was controlled at150° C. The reaction mixture was allowed to gradually cool down to roomtemperature. The resulting crystals were collected by filtration andthen washed with IPA, whereby 1.92 g (6.68 mmol) of the title compoundwere obtained as a brown solid (yield: 70.0%).

(Reaction 4)

1H-2-(1-Methyl-4-nitroimidazol-2-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide

Suspended in 50 ml of DMF were 1.44 g (5.01 mmol) of1H-2-(1-methyl-4-nitroimidazol-2-yl)benzimidazole-5-carboxylic acid,followed by the addition of 0.89 g (5.49 mmol; 1.1 equivalents) of CDI.Under a nitrogen gas atmosphere, the thus-obtained mixture was stirredat room temperature. 2.5 Hours later, the mixture was ice-cooled,followed by the addition of 0.37 ml (5.01 mmol; 1.0 equivalent) ofβ-aminopropionitrile. The temperature of the resulting mixture wasallowed to rise back to room temperature, at which the mixture wasstirred for 5.5 hours and then allowed to stand overnight. The resultantmixture was concentrated under reduced pressure and the residue waswashed with IPA-methanol, whereby 1.36 g (4.0 mmol) of the titlecompound were obtained as ocherous crystals (yield: 80.0%).

m.p.>277° C.

(Reaction 5)

1H-2-(1-Methyl-4-nitroimidazol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in 45 ml of ethanol were 1.35 g (3.98 mmol) of1H-2-(1-methyl-4-nitroimidazol-2-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide. Under ice-cooling, hydrogen chloride gaswas bubbled (for 30 minutes). After saturation, the temperature of theresultant mixture was allowed to rise back to room temperature, at whichthe mixture was stirred for additional two hours. After nitrogen gas wasbubbled for 10 minutes, the thus-obtained mixture was concentrated underreduced pressure. The residue was washed with ethyl ether and the ethylether was then poured out. This procedure was repeated twice. Thethus-obtained solid was suspended in 40 ml of ethanol, through whichammonia gas was bubbled under ice-cooling (for 1.5 hours). Aftersaturation, the temperature of the resultant mixture was allowed to riseback to room temperature, at which it was stirred for 3 hours. Thethus-obtained mixture was the concentrated under reduced pressure. Theresidue was washed with ethanol. The resulting solid was dissolved inethanol/methanol. The solution so obtained was treated with activatedcarbon and then concentrated. The concentrate was washed with methanol,whereby 1.20 g (3.05 mmol) of the title compound were obtained as yellowcrystals (yield: 76.8%).

m.p. 198°-210° C.

(Reaction 6)

1H-2- 1-Methyl-4- 4-N,N-bis(2-chloroethyl)amino!benzoylamino!imidazol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in a mixed solvent of 5 ml of DMF and 3.5 ml of methanol was0.30 g (0.76 mmol) of1H-2-(1-methyl-4-nitroimidazol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride. Using 0.12 g of Pd/C as acatalyst, catalytic hydrogenation was conducted to obtain thecorresponding amino derivative. The amino derivative was dissolved, aswas, in 5 ml of DMF without purification. To the solution, a solution of4- N,N-bis(2-chloroethyl)amino!benzoyl chloride, which had beensynthesized by reacting 0.26 g (0.99 mmol) of 4-N,N-bis(2-chloroethyl)amino!benzoic acid with thionyl chloride, in 2 mlof benzene was added dropwise under a nitrogen gas atmosphere,ice-cooling and stirring. The temperature of the resulting mixture wasallowed to rise back to room temperature, followed by stirring for 5hours. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1) and then crystallized from ethanol, whereby0.07 g (0.12 mmol) of the title compound was obtained as pale yellowcrystals (yield: 15.2%).

m.p. 218°-228° C. (dec.).

IR(KBr)cm⁻¹ : 3415, 1609, 1542, 1315, 1186.

Elemental analysis for C₂₆ H₂₉ N₉ O₂ Cl₂.1.8HCl.3H₂ O: Calculated: C,45.25; H, 5.37; N, 18.27; Cl, 19.52 Found: C, 45.35; H, 5.35; N, 18.16;Cl, 19.52

EXAMPLE 35

(Compound No. 345)

1H-2- 1-Methyl-4- 4-N,N-bis(2-chloroethyl)aminophenyl!butyrylamino!imidazol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in a mixed solvent of 5 ml of DMF and 4 ml of methanol was0.20 g (0.51 mmol) of1H-2-(1-methyl-4-nitroimidazol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride. Using 0.08 g of Pd/C as acatalyst, catalytic hydrogenation was conducted to obtain thecorresponding amino derivative. The amino derivative was dissolved, aswas, in 5 ml of DMF without purification. To the solution, 0.16 g (0.53mmol; 1.03 equivalents) of chlorambucil and 76 mg (0.56 mmol; 1.1equivalents) of HOBt were added successively. The resulting mixture wasice-cooled, followed by the addition of 0.12 g (0.58 mmol; 1.1equivalents) of DCC. The temperature of the mixture so obtained wasallowed to rise back to room temperature, at which the mixture wasstirred for 1.5 hours and then allowed to stand overnight. The reactionmixture was concentrated under reduced pressure. The residue waspurified by chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1→4/2/1; performed twice) and then crystallizedfrom ethanol/ethyl ether, whereby 40 mg (0.061 mmol) of the titlecompound were obtained as light pink crystals (yield: 12.1%).

m.p. 163°-168° C.

IR(KBr)cm⁻¹ : 3409, 2924, 1655, 1560, 1543, 1388, 1019.

Elemental analysis for C₂₉ H₃₅ N₉ O₂ Cl₂.HCl.2H₂ O: Calculated: C,50.85; H, 5.89; N, 18.40 Found: C, 50.94; H, 5.79; N, 18.63

EXAMPLE 36

(Compound No. 358)

1H-2-(1-Methyl-4-formylaminoimidazol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in a mixed solvent of 5 ml of DMF and 5 ml of methanol was0.20 g (0.51 mmol) of1H-2-(1-methyl-4-nitroimidazol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride. Using 0.8 g of Pd/C as acatalyst, catalytic hydrogenation was then conducted. After the Pd/C wasfiltered off, the methanol was distilled out under reduced pressure. Toa DMF solution of the amino derivative obtained above as a crudereaction product, 1-formylimidazole--which had been prepared bydissolving 0.41 g (2.52 mmol) of CDI in 5 ml of THF, adding 0.1 ml (2.65mmol) of formic acid, and then stirring the resultant mixture for 1hour--was added under a nitrogen gas atmosphere, ice-cooling andstirring. The temperature of the resulting mixture was allowed to riseback to room temperature, at which the mixture was stirred for 6 hoursand then allowed to stand overnight. The thus-obtained mixture wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (ethyl acetate/IPA/water=6/2/1).Relevant fractions was further purified on an ODS column (water/5%methanol+acetic acid) and then subjected to gel filtration ("SephadexG-10", water), whereby 26 mg (0.067 mmol) of the title compound wereobtained as amorphous powder (yield: 13.0%).

IR(KBr)cm⁻¹ : 3256, 1684, 1559, 1541, 1398, 1318

Elemental analysis for C₁₆ H₁₈ N₈ O₂.HCl.2H₂ O: Calculated: C, 45.02; H,5.43; N, 22.30 Found: C, 45.39; H, 5.28; N, 22.30

EXAMPLE 37

(Compound No. 1608)

1H-2- 4-(Guanidinoacetyl)amino-1-methylimidazol-2-yl!benzimidazole-5- N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

(Reaction 1)

1H-2-(1-Methyl-4-nitroimidazol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

Dissolved in 5 ml of DMF were 0.17 g (0.59 mmol) of1H-2-(1-methyl-4-nitroimidazol-2-yl)benzimidazole-5-carboxylic acid and0.16 g (0.59 mmol; 1.0 equivalent) ofN,N-bis(2-chloroethyl)-1,4-phenylenediamine hydrochloride. Under anitrogen gas stream, ice-cooling and stirring, 0.25 ml (1.79 mmol; 3.0equivalents) of triethylamine and 0.13 ml (0.86 mmol; 1.5 equivalents)of DECP were added successively to the resultant solution. Thethus-obtained mixture was stirred, as was, for 1 hour and then allowedto stand overnight. It was concentrated under reduced pressure. Theresidue was purified by gel filtration ("Sephadex LH-20", methanol) andthen crystallized from ethanol, whereby 0.16 g (0.32 mmol) of the titlecompound was obtained as yellow crystals (yield: 54.0%).

m.p. 157°-159° C.

(Reaction 2)

1H-2- 4-(Guanidinoacetyl)amino-1-methylimidazol-2-yl!benzimidazole-5- N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

Suspended in a mixed solvent of DMF and methanol was 0.16 g (0.32 mmol)of 1H-2-(1-methyl-4-nitroimidazol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 0.35 ml of 1N hydrochloric acid. Using 10% Pd/C (wet) as acatalyst, the reactant was hydrogenated into the corresponding aminoderivative under normal pressure. To a DMF solution of the aminoderivative, 55 μl (0.39 mmol; 1.2 equivalents) of triethylamine, 0.14 g(0.91 mmol; 3.0 equivalents) of guanidinoacetic acid hydrochloride and0.19 g (0.92 mmol; 3.0 equivalents) of DCC were added successively undera nitrogen gas stream, ice-cooling and stirring. The temperature of thethus-obtained mixture was allowed to rise back to room temperature, atwhich it was stirred for 9 hours and then allowed to stand overnight.The resulting solid was filtered off and the filtrate was concentratedunder reduced pressure. The residue was subjected to gel filtration("Sephadex LH-20", methanol). Eluted fractions were added with 4Nhydrochloric acid/dioxane, concentrated and then crystallized frommethanol, whereby 61 mg (0.095 mmol) of the title compound were obtainedas yellow crystals (yield: 29.6%).

m.p.>250° C.

IR(KBr)cm⁻¹ : 3345, 1670, 1542, 1327.

Elemental analysis for C₂₅ H₂₈ N₁₀ O₂ Cl₂.2.5HCl.1.5H₂ O: Calculated: C,43.53; H, 4.90; N, 20.31; Cl, 23.13 Found: C, 43.43; H, 4.78; N, 20.21;Cl, 23.44

EXAMPLE 38

(Compound No. 424)

1H-2- 2- 4- 4-N,N-Bis(2-chloroethyl)amino!phenyl!butyrylamino!thiophen-4-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

1H-2-(2-Nitrothiophen-4-yl)benzimidazole-5-carboxylic acid.

Dissolved in 100 ml of nitrobenzene were 2.0 g (12.7 mmol) of2-nitrothiophene-4-carboxyaldehyde and 2.0 g (12.8 mmol; 1.0 equivalent)of 3,4-diaminobenzoic acid, followed by stirring under heat over an oilbus which was controlled at 150° C. 32 Hours later, the reaction mixturewas cooled to room temperature. The resulting solid was collected byfiltration and then washed with IPA and methylene chloride, whereby 2.02g (7.78 mmol) of the title compound were obtained as ocherous crystals(yield: 61.2%).

m.p.>270° C.

(Reaction 2)

1H-2-(2-Nitrothiophen-4-yl)benzimidazole-5- N-(2cyanoethyl)!carboxamide

Suspended in 40 ml of DMF were 2.0 g (7.8 mmol) of1H-2-(2-nitrothiophen-4-yl)benzimidazole-5carboxylic acid, followed bythe addition of 1.39 g (8.57 mmol; 1.1 equivalents) of CDI. Theresultant mixture was stirred under a nitrogen gas atmosphere at roomtemperature. 1.5 Hours later, the mixture was ice-cooled, to which 0.63ml (8.54 mmol; 1.1 equivalents) of β-aminopropionitrile was added. Thetemperature of the thus-obtained mixture was allowed rise back to roomtemperature, at which the mixture was allowed to stand overnight. Aftercompletion of the reaction was ascertained, the reaction mixture wasconcentrated under reduced pressure and the residue was washed with IPA,whereby 1.18 g (3.82 mmol) of the title compound were obtained as browncrystals (yield: 49.0%).

m.p.>270° C.

(Reaction 3)

1H-2-(2-Nitrothiophen-4-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in 25 ml of ethanol was 0.85 g (2.7 mmol) of1H-2-(2-nitrothiophen-4-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide. Under ice-cooling, hydrogen chloride gaswas bubbled over 1 hour so that the suspension was saturated withhydrogen chloride gas. The temperature of the thus-obtained mixture wasallowed to rise back to room temperature, at which the mixture wasstirred for additional 2 hours and nitrogen gas was then bubbled for 10minutes. The resultant mixture was concentrated under reduced pressure.The residue was washed with ethyl ether. The residue was then suspendedin 35 ml of ethanol and under ice-cooling, ammonia gas was bubbled for 1hour until saturation. The temperature of the mixture was allowed torise back to room temperature, at which the mixture was allowed to standovernight. The resulting crystals were collected by filtration, whereby0.84 g (2.13 mmol) of the title compound was collected as brown crystals(yield: 78.8%).

m.p.>275° C.

(Reaction 4)

1H-2- 2- 4- 4-N,N-Bis(2-chloroethyl)amino!-phenyl!butyrylamino!thiophen-4-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Dissolved in 4 ml of DMF was 0.15 g (0.38 mmol) of1H-2-(2-nitrothiophen-4-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride. Using 0.07 g of 10% Pd/Cas a catalyst, catalytic hydrogenation was conducted. After the Pd/C wasfiltered off, the filtrate was ice-cooled under a nitrogen gasatmosphere, followed by the dropwise addition of a solution of 0.13 g(0.43 mmol; 1.1 equivalents) of 4- 4-N,N-bis(2-chloroethyl)amino!phenyl!butyryl chloride--which had beenprepared by adding 0.26 g (2.19 mmol; 5.1 equivalents) of thionylchloride to 0.13 g (0.43 mmol; 1.1 equivalents) of chlorambucil,allowing the resultant mixture to stand for 5 minutes at roomtemperature, concentrating the mixture under reduced pressure,evaporating the concentrate with benzene and then repeating theevaporation with benzene once more--in 1 ml of benzene. The temperatureof the resultant mixture was allowed to rise back to room temperature,at which the mixture was stirred for 5.3 hours and then allowed to standovernight. The thus-obtained mixture was concentrated under reducedpressure, purified by chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1) and then crystallized from ethyl ether, whereby13 mg (0.02 mmol) of the title compound were obtained as light browncrystals (yield: 5.25%).

m.p.>275° C.

IR(KBr)cm⁻¹ : 3160, 1637, 1545, 1474, 1289.

EXAMPLE 39

(Compound No. 438)

1H-2-(2-Benzoylaminothiophen-4-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Dissolved in 20 ml of DMF was 0.40 g (1.0 mmol) of1H-2-(2-nitrothiophen-4-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride. Using 0.18 g of 10% Pd/Cas a catalyst, catalytic hydrogenation was conducted. After the Pd/C wasfiltered off, the resultant mixture was ice-cooled under a nitrogen gasatmosphere, followed by the successive addition of 0.16 ml (1.15 mmol;1.1 equivalents) of triethylamine and 0.13 ml (1.13 mmol; 1.1equivalents) of benzoyl chloride. The temperature of the reactionmixture was allowed to rise back to room temperature. 4.5 Hours later,the reaction mixture was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1) and then crystallized from ethyl ether. Asinclusion of impurities was confirmed by NMR, the product was purifiedfurther by gel filtration ("Sephadex LH-20", methanol) and thencrystallized from ethyl ether, whereby 24 mg (0.05 mmol) of the titlecompound were obtained as light brown crystals (yield: 5.0%).

m.p. 220°-223° C.

Elemental analysis for C₂₂ H₂₀ N₆ SO₂.3H₂ O: Calculated: C, 50.52; H,5.20; N, 16.07 Found: C, 50.70; H, 5.02; N, 16.20

EXAMPLE 40

(Compound No. 1617)

1H-2- 5-(Guanidinoacetyl)aminothiophen-3-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

(Reaction 1)

1H-2-(5-Nitrothiophen-3-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

Dissolved in 10 ml of DMF were 0.30 g (1.17 mmol) of1H-2-(5-nitrothiophen-3-yl)benzimidazole-5-carboxylic acid and 0.31 g(1.15 mmol; 1.0 equivalent) ofN,N-bis(2-chloroethyl)-1,4-phenylenediamine hydrochloride. Under anitrogen gas stream, ice-cooling and stirring, 0.49 ml (3.51 mmol; 3.0equivalents) of triethylamine and 0.27 ml (1.78 mmol; 1.5 equivalents)of DECP were added successively. The resultant mixture was stirred, aswas, for 8 hours and then allowed to stand overnight. The mixture wasconcentrated under reduced pressure and methanol was added to theresidue. The insoluble solid was filtered off. The filtrate was purifiedby chromatography on a silica gel column (chloroform/2-4% methanol) andthen washed with methanol, whereby 0.11 g (0.22 mmol) of the titlecompound was obtained as brown crystals (yield: 19.0%).

(Reaction 2)

1H-2- 5-(Guanidinoacetyl)aminothiophen-3-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

Suspended in a mixed solvent of DMF and methanol was 0.10 g (0.20 mmol)of 1H-2-(5-nitrothiophen-3-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 0.22 me of 1N hydrochloric acid. Using 0.05 g of 10% Pd/C(wet) as a catalyst, the reactant was hydrogenated into thecorresponding amino derivative under normal pressure. To a DMF solutionof the amino derivative, 32 μl (0.23 mmol; 1.1 equivalents) oftriethylamine, 93 mg (0.61 mmol; 3.0 equivalents) of guanidinoaceticacid hydrochloride and 0.12 g (0.58 mmol, 2.9 equivalents) of DCC weresuccessively added under a nitrogen gas stream, ice-cooling andstirring. The temperature of the thus-obtained mixture was allowed torise back to room temperature, at which the mixture was stirred for 8hours and then allowed to stand overnight. The resulting solid wasfiltered off and the filtrate was concentrated under reduced pressure.DMF was again added to the residue and the resulting crystals werefiltered off. The filtrate was concentrated and the residue wassubjected to gel filtration ("Sephadex LH-20", methanol). Eluatefractions were added with 4N hydrochloric acid/dioxane, concentrated andthen crystallized from ethanol, whereby 9 mg (0.014 mmol) of the titlecompound were obtained as brown crystals (yield: 7.0%).

m.p.>250° C.

IR(KBr)cm⁻¹ : 3338, 1653, 1517, 1330, 818.

EXAMPLE 41

(Compound No. 505)

1H-2- 5- 4- 4-N,N-Bis(2-chloroethyl)amino!phenyl!butyrylamino!thiophen-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

Methyl 1H-2-(5-nitrothiophen-2-yl)benzimidazole-5-carboxylate

Suspended in 25 ml of nitrobenzene were 0.50 g (3.18 mmol) of5-nitro-2-thiophenecarboxyaldehyde and 0.53 g (3.19 mmol; 1.0equivalent) of methyl 3,4-diaminobenzoate. The resulting mixture wasstirred under heat for 28.5 hours over an oil bath which was controlledat 150° C. The solvent was distilled out and the residue was washed withmethanol, whereby 0.775 g (2.86 mmol) of the title compound was obtainedas ocherous crystals (yield: 89.9%).

m.p.>280° C.

(Reaction 2)

1H-2-(5-Nitrothiophen-2-yl)benzimidazole-5-carboxylic acid

Suspended in 15 ml of methanol was 0.57 g (2.22 mmol) of methyl1H-2-(5-nitrothiophen-2-yl)benzimidazole-5-carboxylate, followed by theaddition of 15 ml of a 1N aqueous solution of sodium hydroxide. Theresultant mixture was stirred at 60° C. for 1 hour under heating. Themethanol was distilled out under reduced pressure. The remaining aqueoussolution was acidified with 4N hydrochloric acid and the resultingcrystals were collected by filtration, whereby 0.55 g (2.14 mmol) of thetitle compound was obtained as dark brown crystals (yield: 96.3%).

m.p.>280° C.

(Reaction 3)

1H-2-(5-Nitrothiophen-2-yl)benzimidazole-5- N-(2-cyanoethyl)!carboxamide

Dissolved in 45 ml of DMF were 1.5 g (5.83 mmol) of1H-2-(5-nitrothiophen-2-yl)benzimidazole-5-carboxylic acid, followed bythe addition of 1.04 g (6.4 mmol; 1.1 equivalents) of CDI. The resultingmixture was stirred at room temperature under a nitrogen gas atmosphereand 1 hour later, was ice-cooled, to which 0.43 ml (5.8 mmol; 1.0equivalent) of β-aminopropionitrile was added. The temperature of thethus-obtained mixture was allowed to rise back to room temperature, atwhich the mixture was stirred for 30 minutes and then allowed to standovernight. After completion of the reaction was confirmed, the reactionmixture was concentrated under reduced pressure. The residue waspurified by chromatography on a silica gel column (methylenechloride/4-10% methanol) and then washed with ethyl ether, whereby 0.53g (1.7 mmol) of the title compound was obtained as yellow crystals(yield: 29.3%).

m.p. 219°-222° C.

(Reaction 4)

1H-2-(5-Nitrothiophen-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in 15 ml of ethanol was 0.52 g (1.68 mmol) of1H-2-(5-nitrothiophen-2-yl)benzimidazole-5-(N-(2-cyanoethyl)!carboxamide,followed by bubbling of hydrogen chloride gas under ice-cooling untilsaturation for an hour. The temperature of the thus-obtained mixture wasallowed to rise back to room temperature and, after the mixture wasstirred for 3 hours, the solvent was distilled out under reducedpressure. The residue was washed with ethyl ether and the ethyl etherwas then poured out. This procedure was repeated twice. The residue wasdissolved in 15 ml of ethanol and under ice-cooling, ammonia gas wasbubbled until saturation (for 2 hours). The temperature of the resultingmixture was allowed to rise back to room temperature, at which themixture was stirred for 1 hour. The solvent was distilled out underreduced pressure and the residue was washed with ethanol, whereby 0.54 g(1.49 mmol) of the title compound was obtained as yellow crystals(yield: 88.6%).

m.p.>280° C.

(Reaction 5)

1H-2-(5-Aminothiophen-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

Suspended in a mixed solvent of 5 ml of DMF and 5 ml of methanol was0.53 g (1.46 mmol) of 1H-2-(5-nitrothiophen-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride. Using 0.22 g of Pd/C as acatalyst, catalytic hydrogenation was conducted to convert the reactantinto the corresponding amino derivative. This amino derivative wasprovided for use in the next reaction as in other examples.

(Reaction 6)

1H-2- 5- 4- 4-N,N-Bis(2-chloroethyl)amino!phenyl!butyrylamino!thiophen-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(5-Aminothiophen-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (half the amount of theamino derivative obtained from 1.46 mmol of the nitro derivative; in theform of a solution dissolved in 3 ml of DMF) was ice-cooled under anitrogen gas atmosphere, to which a solution of 4-N,N-bis(2-chloroethyl)amino!phenylbutyryl chloride--which had beensynthesized from 0.25 g (0.82 mmol; 1.1 equivalents) of chlorambucil and0.49 g (4.1 mmol; 5.5 equivalents) of thionyl chloride--in 2 ml ofmethylene chloride and 0.10 ml (0.72 mmol; 1.0 equivalent) oftriethylamine were added successively. The temperature of thethus-obtained mixture was allowed to rise back to room temperature, atwhich the mixture was stirred for 5 hours and then allowed to standovernight. The resultant mixture was concentrated under reducedpressure, purified by chromatography on a silica gel column (ethylacetate/IPA/water=7/2/1→9/2/1→12/2/1; performed three times in total),and then crystallized from ethyl ether, whereby 27 mg (0.044 mmol) ofthe title compound were obtained as brownish white crystals (yield:6.0%).

m.p.>275° C.

IR(KBr)cm⁻¹ : 3220, 2930, 1684, 1541, 1521, 806.

Elemental analysis for C₂₉ H₃₃ N₇ SO₂ Cl₂.2HCl.H₂ O: Calculated: C,49.37; H, 5.29; N, 13.90 Found: C, 49.69; H, 5.29; N, 13.47

EXAMPLE 42

(Compound No. 518)

1H-2-(5-Formylaminothiophen-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

1H-2-(5-Aminothiophen-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride (half the amount of theamino derivative synthesized from 1.46 mmol of the nitro derivative; inthe form of a solution dissolved in approx. 3 ml of DMF) was ice-cooledunder a nitrogen gas atmosphere, to which a solution offormylimidazole--which had been synthesized by adding 0.14 ml (3.71mmol; 5 equivalents) of formic acid to a solution of 0.59 g (3.63 mmol;5 equivalents) of CDI in 8 ml of THF and then stirring the resultantmixture for 2 hours)--in 8 ml of THF was added dropwise. The temperatureof the thus-obtained mixture was allowed to rise back to roomtemperature, at which the mixture was stirred for 8.5 hours and thenallowed to stand overnight. The resultant mixture was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (ethyl acetate/IPA/water=7/2/1; performed three times) andthen crystallized from ethyl acetate/IPA, whereby 10 mg (0.025 mmol) ofthe title compound were obtained as brown powder (amorphous) (yield:3.4%).

EXAMPLE 43

(Compound No. 3024)

1H-2-(5-Nitrofuran-2-yl)benzimidazole-5-carboxylic acid

Suspended in 25 ml of nitrobenzene were 0.50 g (3.54 mmol) of5-nitrofurfural and 0.56 g (3.57 mmol; 1.0 equivalent) of3,4-diaminobenzoic acid (97%), followed by stirring under heat for 20hours over an oil bath which was controlled at 150° C. The thus-obtainedmixture was ice-cooled and the resulting crystals were collected byfiltration, whereby 0.64 g (2.32 mmol) of the title compound wasobtained as dark brown crystals. Further, the filtrate was concentratedand washed with methylene chloride, whereby 0.89 g (3.28 mmol) of thetitle compound was obtained (yield: 92.7%).

m.p.>280° C.

EXAMPLE 44

(Compound No. 672)

1H-2-(5-Benzoylaminopyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

(Reaction 1)

1H-2-(5-Nitropyrrol-2-yl)benzimidazole-5-carboxylic acid

A solution of 1.03 g (7.35 mmol) of 5-nitropyrrol-2-aldehyde and 1.12 g(7.35 mmol) of 3,4-diaminobenzoic acid in 50 mg of nitrobenzene washeated at 150° C. for 6 hours. After completion of the reaction, theresulting crystals were collected by filtration and washed with IPA.They were recrystallized from DMF-water, whereby 1.28 g of the titlecompound were obtained as green crystals (yield: 64%).

m.p.>300° C.

IR(KBr)cm⁻¹ : 3269, 2835, 1665, 1493, 1458, 1350, 1306, 1254, 1137.

(Reaction 2)

1H-2-(5-Nitro-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide

CDI (566 mg; 3.49 mmol) was added to a solution of 633 mg (2.33 mmol) of1H-2-(5-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid in 19 ml ofDMF, followed by stirring at room temperature for 30 minutes. Aftercrystals were sufficiently precipitated and full consumption of the rawmaterials was confirmed by TLC, 489 mg (6.98 mmol) of3-aminopropionitrile were added dropwise. The resulting mixture wasstirred at room temperature for 30 minutes until the crystals weredissolved. After completion of the reaction, the reaction mixture wasconcentrated and IPA was added. The precipitated crystals were collectedand then recrystallized from DMF-water, whereby 608 mg of the titlecompound were obtained as ocherous crystals (yield: 80%).

m.p. 268°-270° C.

IR(KBr)cm⁻¹ : 3359, 2252, 1630, 1545, 1351, 1305.

(Reaction 3)

1H-2-(5-Nitropyrrol-2-yl)benzimidazole-5- N-(2-amidinoethyl)!carboxamidehydrochloride

A suspension of 771 mg (2.38 mmol) of1H-2-(5-nitro-1-methylpyrrol-2-yl)benzimidazole-5-N-(2-cyanoethyl)!carboxamide in 54 ml of ethanol was saturated withhydrogen chloride gas under ice-cooling. The resultant mixture wasstirred at room temperature for 1 hour. After excess hydrogen chloridegas purged with nitrogen gas, the mixture was concentrated and theresidue was washed with ethyl ether. The residue was again suspended in23 ml of a 1:1 mixed solvent of methanol and ethanol, followed bysaturated with ammonia gas. As a result, crystals were precipitatedsubsequent to initial dissolution of the residue. After nitrogen gas wasbubbled to purge excess ammonia gas, crystals were collected byfiltration and then washed with IPA, whereby 812 mg of the titlecompound were obtained as pale yellow crystals (yield: 90%).

m.p. 299°-300° C.

IR(KBr)cm⁻¹ : 3363, 1702, 1636, 1545, 1452, 1405, 1349, 1236, 1193.

(Reaction 4)

1H-2-(5-Benzoylaminopyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

A solution of 153 mg (0.405 mmol) of1H-2-(5-nitropyrrol-2-yl)benzimidazole-5- N-(2-amidinoethyl)!carboxamidehydrochloride in 4.6 ml of DMF was catalytically hydrogenated using 76.9mg of 10% Pd/C as a catalyst, so that the reactant was reduced into thecorresponding amino compound. The Pd/C was filtered off. To thefiltrate, 56.9 mg (0.405 mmol) of benzoyl chloride were added dropwiseat -78° C. under a nitrogen gas atmosphere, followed by stirring for 30minutes. The reaction mixture was concentrated and the residue wassubjected to chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1), whereby 56.4 mg of the title compound wereobtained (yield: 31%).

m.p. 195°-200° C.

IR(KBr)cm⁻¹ : 3316, 1687, 1638, 1555, 1432, 1307.

EXAMPLE 45

(Compound No. 671)

1H-2-(5-Formylaminopyrrol-2-yl)benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

A solution of 102 mg (0.270 mmol) of1H-2-(5-nitropyrrol-2-yl)benzimidazole-5- N-(2-amidinoethyl)!carboxamidehydrochloride in 3.1 ml of DMF was catalytically hydrogenated using 10%Pd/C as a catalyst, so that the reactant was reduced into thecorresponding amino compound. The Pd/C was filtered off. Added dropwiseat -40° C. to the filtrate under a nitrogen gas atmosphere was a THFsolution of N-formylimidazole, which THF solution had been prepared byadding 24.9 mg (0.54 mmol) of 98-100% formic acid dropwise at roomtemperature to a solution of 87.6 mg (0.54 mmol) of CDI in 2.6 ml of THFand then stirring the resultant mixture for 15 minutes. After thethus-obtained mixture was stirred at room temperature for 15 minutes,the reaction mixture was concentrated and then subjected to flush columnchromatography (ethyl acetate/IPA/water=6/2/1), whereby 7.2 mg of thetitle compound were obtained (yield: 7.1%).

m.p. 175°-185° C. (dec.).

IR(KBr)cm⁻¹ : 3406, 1671, 1630, 1561, 1438, 1319.

EXAMPLE 46

(Compound No. 665)

1H-2- 5- 4- 4-N,N-Bis(2-chloroethyl)amino!phenyl!butyrylamino!pyrrol-2-yl!benzimidazole-5-N-(2-amidinoethyl)!carboxamide hydrochloride

A solution of 111 mg (0.294 mmol) of1H-2-(5-nitropyrrol-2-yl)benzimidazole-5- N-(2-amidinoethyl)!carboxamidehydrochloride in 3.3 ml of DMF was catalytically hydrogenated using 55.8mg of 10% Pd/C as a catalyst, so that the reactant was reduced into thecorresponding amino compound. The Pd/C was filtered off. Added dropwiseat -78° C. to the filtrate under a nitrogen gas atmosphere was a1,2-dichloroethane solution of 4- 4-N,N-bis(2-chloroethyl)amino!phenyl!butyryl chloride, which1,2-dichloroethane solution had been prepared by adding 153 mg (1.20mmol) of oxalyl chloride dropwise at -20° C. to a solution of 122 mg(0.401 mmol) of chlorambucil in 6.1 ml of 1,2-dichloroethane, stirringthe resultant mixture overnight at room temperature, concentrating theresultant mixture into dryness and then dissolving the thus-obtained oilin 1.0 ml of 1,2-dichloroethane. The thus-obtained mixture was stirredfor 30 minutes. After completion of the reaction, the reaction mixturewas concentrated and the residue was subjected to flush columnchromatography (ethyl acetate/IPA/water=6/2/1), whereby 45.6 mg of thetitle compound were obtained (yield: 24%).

m.p. 150°-156° C. (dec.).

IR(KBr)cm⁻¹ : 3269, 3133, 1655, 1557, 1519, 1438, 1313, 1044.

EXAMPLE 47

(Compound No. 1592)

1H-2- 4-(Guanidinoacetyl)amino-1-methylpyrrol-2-yl!benzimidazole-5- N-3- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!carboxamido!propyl!!carboxamidehydrochloride

(Reaction 1)

4-1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole!-5-carboxamido!butyricacid

Suspended in 10 ml of DMF was 0.30 g (1.05 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid,followed by the addition of 0.25 g (1.54 mmol; 1.5 equivalents) of CDIunder a nitrogen gas stream. The thus-obtained mixture was stirred, aswas, at room temperature for 1.5 hours. The mixture was ice-cooled, towhich 0.13 g (1.26 mmol; 1.2 equivalents) of γ-aminobutyric acid wasadded. The temperature of the mixture was allowed to rise back to roomtemperature, at which the mixture was stirred for 6.5 hours and thenallowed to stand overnight. The mixture was concentrated under reducedpressure and methanol was added to the residue. The resulting crystalswere collected by filtration, whereby 0.29 g (0.78 mmol) of the titlecompound was obtained as yellow crystals (yield: 74.4%).

(Reaction 2)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!carboxamido!propyl!!carboxamide

Dissolved in 10 mL of DMF were 0.24 g (0.65 mmol) of 4-1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole!-5-carboxamido!butyricacid and 0.19 g (0.70 mmol; 1.08 equivalents) of 4-N,N-bis(2-chloroethyl)!phenylenediamine hydrochloride. The resultantmixture was stirred under a nitrogen gas stream and ice-cooling.Successively added were 0.27 ml (1.94 mmol; 3.0 equivalents) oftriethylamine and 0.15 ml (0.99 mmol; 1.5 equivalents) of DECP. Thetemperature of the thus-obtained mixture was allowed to rise back toroom temperature, at which the mixture was stirred for 5 hours and thenallowed to stand overnight. The resulting mixture was concentrated underreduced pressure and the residue was crystallized from methanol, whereby0.26 g (0.45 mmol) of the title compound was obtained as pale yellowcrystals (yield: 69.3%).

(Reaction 3)

1H-2- 4-(Guanidinoacetyl)amino-1-methylpyrrol-2-yl!benzimidazole-5- N-3- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!carboxamido!propyl!!carboxamidehydrochloride

Using 10% Pd/C (wet) as a catalyst, 0.25 g (0.43 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!carboxamido!propyl!!carboxamide washydrolyzed into the corresponding amino derivative under normalpressure. A DMF solution of the amino derivative was stirred under anitrogen gas stream and ice-cooling, to which 68 μl (0.49 mmol; 1.1equivalents) of triethylamine, 0.20 g (1.30 mmol; 3.0 equivalents) ofguanidinoacetic acid hydrochloride and 0.27 g (1.31 mmol; 3.0equivalents) of DCC were added successively. The temperature of thethus-obtained mixture was allowed to rise back to room temperature, atwhich the mixture was stirred for 4 hours and then allowed to standovernight. The mixture was concentrated under reduced pressure. Theresidue was subjected to gel filtration ("Sephadex LH-20", methanol),purified further by chromatography on a silica gel column (ethylacetate/IPA/water=6/2/1) and then crystallized from IPA, whereby 88 mg(0.127 mmol) of the title compound were obtained as white crystals(yield: 29.6%).

IR(KBr)cm⁻¹ : 3317, 1655, 1542, 1518, 1248

Elemental analysis for C₃₀ H₃₆ N₁₀ O₃ Cl₂.HCl.3H₂ O.0.5IPA: Calculated:C, 48.75; H, 6.10; N, 18.05; Cl, 13.70 Found: C, 48.79, H, 5.82; N,17.67; Cl, 13.67

EXAMPLE 48

(Compound No. 1017)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-chloro-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

(Reaction 1)

4- N,N-Bis(2-hydroxyethyl)amino!-3-chloro-nitrobenzene

Dissolved in 8 ml of DMSO were 10.0 g (57.0 mmol) of3-chloro-4-fluronitrobenzene and 8.6 g (82 mmol) of diethanolamine. Thethus-obtained mixture was stirred under heat for 2 hours at 140° C.,followed by extraction with ethyl acetate. The solvent was distilled outunder reduced pressure, whereby 9.5 g of the title compound wereobtained as a yellow oil (yield: 64%).

(Reaction 2)

4- N,N-Bis(2-chloroethyl)amino!-3-chloro-nitrobenzene

Thionyl chloride (6 ml; 82 mmol) was added to a solution of 4.2 g (16.1mmol) of 4- N,N-bis(2-hydroxyethyl)!amino-3-chloronitrobenzene in 60 mlof 1,2-dichloroethane. The thus-obtained mixture was stirred under heatfor 1 hour at 80° C. and the solvent was then distilled out underreduced pressure, whereby 4.0 g of the title compound were obtained as ayellow oil (yield: 83%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-chloro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

Dissolved in 10 ml of DMF were 200 mg (0.7 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and3-chloro-4- N,N-bis(2-chloroethyl)amino!aniline hydrochloride which hadbeen obtained by catalytically hydrogenating 230 mg (0.49 mmol) of 4-N,N-bis(2-chloroethyl)amino!-3-chloro-nitrobenzene in 20 ml of methanolwhile using 100 mg of 10% Pd/C as a catalyst. The thus-obtained solutionwas cooled to 0° C. Under a nitrogen gas atmosphere, were added 117 μl(0.84 mmol) of triethylamine and then 127 μl (0.84 mmol) of DECP. Theresultant mixture was stirred, as was, for 40 minutes. The mixture wasstirred further for 1 hour at room temperature and then allowed to standovernight. The solvent was distilled out under reduced pressure. Theresidue was purified by chromatography on a silica gel column (ethylacetate/n-hexane=1/1), whereby 210 mg of the title compound wereobtained as yellow powder (yield: 51%).

(Reaction 4)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-chloro-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

Dissolved in 10 ml of a 1:1 mixed solvent of DMF and methanol were 200mg (0.37 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-3-chloro-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide in areactor, followed by the addition of 200 mg of 10% Pd/C and 420 μl of 1Nhydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with hydrogen gas and the mixture was stirred at room temperaturefor 2 hours. After the Pd/C was filtered off, the filtrate wasconcentrated and the resultant concentrate was dissolved in DMF to forma DMF solution. To the solution, 62 μl (0.45 mmol) of triethylamine, 172mg (1.12 mmol) of guanidinoacetic acid hydrochloride and 231 mg (1.12mmol) of DCC were successively added under ice-cooling. Thethus-obtained mixture was stirred at room temperature for 1 hour andthen allowed to stand overnight. After the resulting white precipitatewas filtered off, the solvent was distilled out under reduced pressure.A 4N hydrochloric acid/dioxane solution was added to the residue,followed by concentration under reduced pressure. The residue was washedwith IPA. Yellow powder so obtained was washed further with ethanol,whereby 100 mg of the title compound were obtained as yellow powder(yield: 42%).

IR(KBr)cm⁻¹ : 3151, 1654, 1500, 1397, 1061, 824

EXAMPLE 49

(Compound No. 1021)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-fluoro-4- N,N-bis(2-chloroethyl)amino!phenyl!carboxamide hydrochloride

Dissolved in a mixed solvent of 10 ml of DMF and 10 ml of methanol were150 mg (0.29 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N- 3-fluoro-4- N,N-bis(2-chloroethyl)amino!phenyl!carboxamide, followedby the addition of 200 mg of 10% Pd/C and 300 μl of 1N hydrochloric acidunder a nitrogen gas atmosphere. Hydrogenation was then conducted atroom temperature under normal pressure. After the Pd/C was filtered off,the filtrate was concentrated and the resultant concentrate wasdissolved in DMF to form a DMF solution. To the solution, 49 μl (0.29mmol) of triethylamine, 133 mg (0.87 mmol) of guanidinoacetic acidhydrochloride and 180 mg (0.87 mmol) of DCC were successively addedunder ice-cooling. Subsequent to the reaction, the reaction mixture wasfiltered and the filtrate was concentrated. The brown syrupy residue wassubjected to chromatography on a gel filtration column ("SephadexLH-20", methanol). Fluorescent fractions were collected andconcentrated, followed by the addition of 4N hydrochloric acid/dioxane.The resulting mixture was concentrated again. The concentrate was washedwith methanol, whereby 76.5 mg of the title compound were obtained asyellow powder (yield: 40%).

Elemental analysis for C₂₆ H₂₈ Cl₂ FN₉ O₂.2HCl: Calculated: C, 47.22, H,4.57; N, 19.06 Found: C, 47.60, H, 4.53; N, 18.81

EXAMPLE 50

(Compound No. 1013)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-cyano-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

(Reaction 1)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-cyano-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

Dissolved in 5 ml of DMF were 105 mg (0.37 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and3-cyano-4- N,N-bis(2-chloroethyl)amino!aniline hydrochloride which hadbeen obtained by hydrogenating a solution of 104 mg (0.36 mmol) of 2-N,N-bis(2-chloroethyl)amino!-5-nitrobenzonitrile in 10 ml of methanolwhile using 100 mg of 10% Pd/C. The thus-obtained solution was cooled to0° C. Under a nitrogen gas atmosphere, were added 61 μl (0.44 mmol) oftriethylamine and then 67 μl (0.44 mmol) of DECP. The resultant mixturewas stirred, as was, for 30 minutes. After the mixture was stirred atroom temperature for additional 2 hours, the solvent was distilled outunder reduced pressure. The residue was purified by chromatography on asilica gel column (chloroform/methanol=10/1), whereby 61 mg of the titlecompound were obtained as yellow powder (yield: 32%).

(Reaction 2)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-cyano-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

Dissolved in 10 ml of a 1:1 mixed solvent of DMF and methanol were 56 mg(0.11 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-3-cyano-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide in a reactor,followed by the addition of 50 mg of 10% Pd/C and 128 μl (1.2equivalents) of 1N hydrochloric acid under a nitrogen gas atmosphere.The reactor was purged with hydrogen gas, followed by stirring at roomtemperature for 2 hours. After the Pd/C was filtered off, the filtratewas concentrated to form a DMF solution. To the solution, 18 μl (0.13mmol) of triethylamine, 50 mg (0.33 mmol) of guanidinoacetic acidhydrochloride and 70 mg (0.34 mmol) of DCC were successively added underice-cooling. The resultant mixture was stirred at room temperature for 1hour and then allowed to stand overnight. The resulting whiteprecipitate was filtered off and the solvent was distilled out underreduced pressure. The residue was dissolved in methanol and purified bygel filtration ("Sephadex LH-20", methanol). After the solvent wasdistilled out under reduced pressure, a 4N hydrochloric acid/dioxanesolution was added. The thus-obtained mixture was concentrated againunder reduced pressure. The residue was dissolved in methanol, to whichethyl acetate was added to conduct reprecipitation, whereby 27 mg of thetitle compound were obtained as white powder (yield: 38%).

IR(KBr)cm⁻¹ : 3146, 2216, 1656, 1506, 1399, 1059, 823

EXAMPLE 51

(Compound No. 1596)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-4-N,N-bis(2-chloroethyl)amino!-2-morphonylcarboxamido!phenyl!carboxamidehydrochloride

(Reaction 1)

N-(2-Nitro-5-chlorobenzoyl)morpholine

Dissolved in 20 ml of thionyl chloride were 5.0 g (24.8 mmol) of2-nitro-5-chlorobenzoic acid, followed by heating for 1.5 hours underreflux. After the reaction, the reaction mixture was concentrated andthe residue was dissolved in 10 ml of acetone. The thus-obtainedsolution was added dropwise to a solution of 4.7 ml (62 mmol) ofmorpholine in 20 ml of acetone, followed by stirring at room temperaturefor 2 hours. Subsequent to the reaction, the reaction mixture wasconcentrated and then extracted with ethyl acetate. The ethyl acetatelayer was dried and then concentrated. The residue was recrystallizedfrom ethyl acetate/n-hexane, whereby 5.64 g of the title compound wereobtained as white powder (yield: 84%).

(Reaction 2)

N- 2-Nitro-5- N,N-bis(2-hydroxyethyl)amino!benzoyl!morpholine

Dissolved in 4 ml of DMSO were 1.0 g (3.69 mmol) ofN-(2-nitro-5-chlorobenzoyl)morpholine and 1.16 g (11 mmol) ofdiethanolamine. The resulting mixture was stirred under heat at 140° C.for 3 hours. After the reaction, the reaction mixture was concentratedand the resulting yellow syrup was purified by chromatography on asilica gel column (chloroform/methanol=10/1), whereby 667 mg of thetitle compound were obtained as yellow powder (yield: 53.5%).

(Reaction 3)

N- 2-Nitro-5- N,N-bis(2-chloroethyl)amino!benzoyl!morpholine

Dissolved in 5 ml of DMF were 500 mg (1.5 mmol) of N- 2-nitro-5-N,N-bis(2-hydroxyethyl)amino!benzoyl!morpholine, followed by thedropwise addition of 414 mg (3.6 mmol) of methanesulfonyl chloride underice-cooling. The thus-obtained mixture was stirred under heat at 70° C.for 1 hour. After the reaction, the reaction mixture was concentratedand the residue was purified by chromatography on a silica gel column(chloroform), whereby 539 mg of the title compound were obtained asyellow powder (yield: 81%).

(Reaction 4)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!-2-morphonylcarboxamido!phenyl!carboxamide

Dissolved in 10 ml of THF were 200 mg (0.56 mmol) of N- 2-nitro-5-N,N-bis(2-chloroethyl)amino!benzoyl!morpholine, followed by the additionof 200 mg of 10% Pd/C under a nitrogen gas atmosphere. 4N Hydrochloricacid (140 μl) was added, followed by hydrogenation at room temperatureunder normal pressure. After the Pd/C was filtered off, the filtrate wasconcentrated. The concentrate was added with 160 mg (0.56 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid,followed by the successive addition of 120 μl (0.84 mmol) of DECP and210 μl (1.5 mmol) of triethylamine. The thus-obtained mixture wasallowed to stand overnight. After the reaction, the reaction mixture wasconcentrated and the resulting black brown syrup was purified bychromatography on a silica gel column (chloroform→chloroform+2%methanol), whereby 100 mg of the title compound were obtained as yellowpowder (yield: 31%).

(Reaction 5)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-4-N,N-bis(2-chloroethyl)amino!-2-morpholinylcarboxamido!phenyl!carboxamidehydrochloride

Dissolved in a mixed solvent of 10 ml of DMF and 10 ml of methanol were100 mg (0.17 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N- 4-N,N-bis(2-chloroethyl)amino!-2-morpholinylcarboxamido!phenyl!carboxamide,followed by the addition of 100 mg of 10% Pd/C and 180 μl of 1Nhydrochloric acid under a nitrogen gas atmosphere. Hydrogenation wasthen conducted at room temperature under normal pressure. After the Pd/Cwas filtered off, the filtrate was concentrated to form a DMF solution.To the solution, 28 μl (0.17 mmol) of triethylamine, 77 mg (0.50 mmol)of guanidinoacetic acid hydrochloride and 103 mg (0.5 mmol) of DCC weresuccessively added under ice-cooling. The thus-obtained mixture wasallowed to stand overnight. Subsequent to the reaction, the reactionmixture was filtered and the filtrate was concentrated. The resultingbrown syrupy residue was subjected to chromatography on a gel filtrationcolumn ("Sephadex LH-20", methanol). 4N Hydrochloric acid/dioxane wasadded, followed by concentration again. The residue was washed withmethanol, whereby 25 mg of the title compound were obtained as yellowpowder (yield: 20%).

EXAMPLE 52

(Compound No. 1042)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-2- N- (N,N-dimethylamino)ethyl!carboxamido!-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

(Reaction 1)

N- (N,N-Dimethylamino)ethyl!-2-chloro-5-nitrobenzamide

A solution of 10 g (0.050 mmol) of 2-chloro-5-nitrobenzoic acid in 60 mlof THF was cooled over an ice bath, followed by the addition of 10 g(0.064 mmol) of CDI. The thus-obtained mixture was stirred at roomtemperature for 1 hour. To the solution, 12 ml (0.11 mmol) ofN,N-dimethylethylenediamine were added dropwise, followed by stirring atroom temperature for 3 hours. After the solvent was distilled out, theresidue was dissolved in ethyl acetate. After the solution so obtainedwas washed with a 10% aqueous solution of sodium hydrogencarbonate,magnesium sulfate was added to the solution to dry the same. The ethylacetate was distilled out under reduced pressure and the residue waspurified by chromatography on a silica gel column (ethyl acetate),whereby 10 g of the title compound were obtained as a colorless oil(yield: 74%).

(Reaction 2)

N- (N,N-Dimethylamino)ethyl!-2-N,N-bis(2-hydroxyethyl)amino!-5-nitrobenzamide

Diethanolamine (5 g; 48.6 mmol) was added to a solution of 5 g (18.4mmol) of N- (N,N-dimethylamino)ethyl!-2-chloro-5-nitrobenzamide in 10 mlof DMSO, followed by stirring at 150° C. for 3.5 hours. After theresulting mixture was cooled to room temperature, it was extracted withethyl acetate. Magnesium sulfate was added to the extract to dry thesame, and the solvent was then distilled out under reduced pressure. Theresidue was purified by chromatography on a silica gel column (ethylacetate/methanol=1/0→1/1), whereby 2.6 g of the title compound wereobtained as a colorless oil (yield: 38%).

(Reaction 3)

N- (N,N-Dimethylamino)ethyl!-2-N,N-bis(2-chloroethyl)amino!-5-nitrobenzamide

Triethylamine (4.5 ml; 32 mmol) was added to a solution of 2.6 g (0.76mmol) of N- (N,N-dimethylamino)ethyl!-2-N,N-bis(2-hydroxyethyl)amino!-5-nitrobenzamide in 20 ml of methylenechloride, followed by cooling over an ice bath. The thus-obtainedsolution was added with 1.8 ml (23 mmol) of mesyl chloride, followed bystirring at room temperature for 3 hours. After the reaction mixture waswashed with a saturated aqueous solution of sodium hydrogencarbonate,magnesium sulfate was added to the organic layer to dry the same. Thesolvent was distilled out under reduced pressure. The residue wasdissolved in 10 ml of DMF, to which 5 g of sodium chloride were added.The resulting mixture was then stirred at 150° C. for 30 minutes. Afterthe thus-obtained mixture was cooled to room temperature, the sodiumchloride was filtered off and the solvent was distilled out underreduced pressure. The residue was purified by chromatography on a silicagel column (chloroform/methanol=10/1), whereby 0.95 g of the titlecompound was obtained as yellow powder (yield: 33%).

(Reaction 4)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2- N-(N,N-dimethylamino)ethyl!carboxamido!-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

Dissolved in 10 ml of DMF were 500 mg (1.8 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and 2-N- (N,N-dimethylamino)ethyl!carboxamido!-4-N,N-bis(2-chloroethyl)amino!aniline hydrochloride which had beenobtained by catalytically hydrogenating 200 mg (0.53 mmol) of N-(N,N-dimethylamino)ethyl!-5-N,N-bis(2-chloroethyl)amino!-2-nitrobenzamide in 10 ml of methanol. Thethus-obtained solution was cooled to 0° C. Added under a nitrogen gasatmosphere were 241 μl (1.8 mmol) of triethylamine and then 265 μl (1.8mmol) of DECP. The resulting mixture was stirred, as was, for 30minutes. The mixture was stirred further for 1 hour at room temperatureand then allowed to stand overnight. The solvent was distilled out underreduced pressure and the residue was purified by chromatography on asilica gel column (chloroform/methanol=1/1), whereby 96 mg of the titlecompound were obtained as yellow powder (yield: 30%).

(Reaction 5)

1H-2-(1-Methyl-4-guanidinoacetylamino)pyrrol-2-yl)benzimidazole-5- N- 2-N- (N,N-dimethylamino)ethyl!carboxamido!-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

Dissolved in a 1:1 mixed solvent of DMF and methanol in a reactor were96 mg (0.16 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N- 2- N- (N,N-dimethylamino)ethyl!carboxamido!-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 100 mg of 10% Pd/C and 600 μl of 1N hydrochloric acid undera nitrogen gas atmosphere. The reactor was purged with hydrogen gas,followed by stirring at room temperature for 2 hours. After the Pd/C wasfiltered off, the filtrate was concentrated to form a DMF solution. Tothe solution, 26 μl (0.19 mmol) of triethylamine, 72 mg (0.47 mmol) ofguanidinoacetic acid hydrochloride, 97 mg (0.47 mmol) of DCC and 36 mg(0.24 mmol) of HOBt were successively added under ice-cooling. Thethus-obtained mixture was stirred at room temperature for 1 hour andthen allowed to stand overnight. The resulting white precipitate wasfiltered off and the solvent was distilled out under reduced pressure.The residue was purified by chromatography on a silica gel column (ethylacetate/IPA/water=4/2/1), whereby 50 mg of the title compound wereobtained as yellow powder (yield: 42%).

IR(KBr)cm⁻¹ : 1654, 1525, 1396, 1063, 821

EXAMPLE 53

(Compound No. 1584)

1H-2- 1-Methyl-4-(arginylamino)pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

(Reaction 1)

1H-2- 1-Methyl-4-N-t-butoxycarbonyl)arginyl!amino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

Dissolved in a mixed solvent of 3 ml of DMF and 3 ml of methanol was0.41 g (0.82 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N- 4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 0.21 ml of 4N hydrochloric acid. Using 0.18 g of 10% Pd/C asa catalyst, the reactant was converted to the corresponding aminoderivative by hydrogenation under normal pressure. A DMF solution of theamino derivative was stirred under a nitrogen gas stream andice-cooling, to which 0.12 ml (0.86 mmol; 1.05 equivalents) oftriethylamine, 0.51 g (1.64 mmol; 2.0 equivalents) of N-Boc arginine and0.34 g (1.65 mmol; 2.0 equivalents) of DCC were added successively. Thethus-obtained mixture was stirred, as was, for 2 hours and then allowedto stand overnight. The resulting crystals were filtered off and thefiltrate was concentrated under reduced pressure. The residue waspurified by chromatography on a silica gel column (ethylacetate/IPA/water=7/2/1 and then chloroform/15-20% methanol; performedtwice in total) and was then crystallized from ether, whereby 80 mg(0.11 mmol) of the title compound were obtained as light brown crystals(yield: 12.8%).

(Reaction 2)

1H-2- 1-Methyl-4-(arginylamino)pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

Dissolved in 4 ml of ethanol was 1H-2- 1-methyl-4-N-t-butoxycarbonyl)arginyl!amino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 1 ml of 4N hydrochloric acid/dioxane. The thus-obtainedmixture was stirred at room temperature for 5 hours and thenconcentrated under reduced pressure. The residue was subjected to gelfiltration ("Sephadex LH-20", methanol) and then crystallized fromacetonitrile, whereby 50 mg (0.71 mmol) of the title compound wereobtained as yellow crystals (yield: 67.6%).

m.p.>275° C.

IR(KBr)cm⁻¹ : 3384, 1654, 1541, 1518

Elemental analysis for C₂₉ H₃₆ N₁₀ O₂ Cl₂.2HCl.4.5H₂ O: Calculated: C,42.58; H, 5.91; N, 17.12 Found: C, 43.09, H, 5.76; N, 16.84

EXAMPLE 54

(Compound No. 1585)

1H-2- 1-Methyl-4-(4-benzylpiperazinyl)acetylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a mixed solvent of 5 ml of DMF and 5 ml of methanol, 0.31 g (0.62mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)!amino!phenyl!!carboxamide was dissolved, followedby the addition of 0.7 ml of 1N hydrochloric acid. Using 0.14 g of 10%Pd/C (wet) as a catalyst, the resultant mixture was hydrogenated undernormal pressure so that it was converted to the corresponding aminoderivative. A solution of the amino derivative in DMF was stirred undera nitrogen gas atmosphere and ice-cooling. To the reaction mixture, 0.1ml (0.72 mmol; 1.2 equivalents) of triethylamine and2-(4-benzylpiperazino)acetylimidazole, which had been prepared bydissolving 0.47 g of 2-(4-benzylpiperazino)acetic acid (with someimpurities) and 0.15 g (0.93 mmol) of CDI in 5 ml of DMF, were added.The mixture was stirred for 4 hours and was then allowed to standovernight as was. The thus-obtained mixture was concentrated underreduced pressure and the residue was purified by chromatography on asilica gel column (chloroform/4% methanol). The reaction product wasrecrystallized from ethyl ether, whereby 0.25 g (0.36 mmol) of the titlecompound was obtained as light red crystals (yield: 58.6%).

m.p. 185°-195° C. (dec.).

IR(KBr)cm⁻¹ : 3284, 1654, 1518, 1327, 815

Elemental analysis for C₃₆ H₄₀ N₈ O₂ Cl₂.H₂ O: Calculated: C, 61.27; H,6.00; N, 15.88 Found: C, 61.14, H, 5.75; N, 15.95

EXAMPLE 55

(Compound No. 1576)

1H-2- 1-Methyl-4- (piperazinylacetyl)amino!pyrrol-2-yl!benzimidazole-5-N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a mixed solvent of 3 ml of DMF and 3 ml of methanol, 0.24 g (0.35mmol) of 1H-2- 1-methyl-4-(4-benzylpiperazinyl)acetylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide was suspended. Using0.12 g of 10% Pd/C (wet) as a catalyst, catalytic hydrogenation wasconducted. Eleven hours later, the reaction was terminated even thoughsome raw materials still remained. After Pd/C was filtered off, thefiltrate was subjected to gel filtration ("Sephadex LH-20", methanol).To the fraction so eluted, 4N hydrochloric acid/dioxane was added,followed by crystallization from ethanol. As the crystals stillcontained some impurities, they were purified further by chromatographyon a silica gel column (DMF/toluene=1/1) and crystallized from ethylether, whereby 103 mg (0.17 mmol) of the title compound were obtained asyellowish white crystals (yield: 49.1%).

m.p.>250° C.

IR(KBr)cm⁻¹ : 3401, 1654, 1518, 815

Elemental analysis for C₂₉ H₃₄ N₈ O₂ Cl₂.2HCl.1.5H₂ O.1.5EtOH:Calculated: C, 50.01: H, 5.88; N, 15.55 Found: C, 49.94, H, 5.46; N,15.62

EXAMPLE 56

(Compound No. 1590)

1H-2- 1-Methyl-4- 2-imidazolylcarboxamido)-pyrrol-2-yl!benzimidazole-5-N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a mixed solvent of 3 ml of DMF and 3 ml of methanol, 0.20 g (0.40mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide was dissolved, followedby the addition of 0.5 ml of 1N hydrochloric acid. Using 0.10 g of 10%Pd/C (wet) as a catalyst, the resultant mixture was hydrogenated undernormal pressure so that it was converted to the corresponding aminoderivative. A solution of the amino derivative in DMF was stirred undera nitrogen gas atmosphere and ice-cooling. To the reaction mixture, 68μl (0.49 mmol; 1.2 equivalents) of triethylamine, 0.11 g (0.98 mmol; 2.5equivalents) of imidazole-2-carboxylic acid, 59 mg (0.44 mmol; 1.1equivalents) of HOBt and 92 mg (0.45 mmol; 1.1 equivalents) of DCC wereadded. The temperature of the resultant mixture was allowed to rise backto room temperature, at which the mixture was stirred for 4 hours. Thereaction mixture was then allowed to stand overnight. After the solid soobtained was filtered off, the filtrate was concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (chloroform/4-8% methanol). Eluted fractions were concentratedand the residue was added with 4N hydrochloric acid/dioxane. Theresulting solution was concentrated and was then crystallized frommethanol, whereby 74 mg (0.13 mmol) of the title compound was obtainedas light brown crystals (yield: 32.7%).

m.p.>260° C.>.

IR(KBr)cm⁻¹ : 3365, 1684, 1592, 1517, 1398, 1329, 818

Elemental analysis for C₂₇ H₂₆ N₈ O₂ Cl₂.2HCl.2.5H₂ O: Calculated: C,47.45; H, 4.87; N, 16.40 Found: C, 47.43, H, 4.98; N, 16.30

EXAMPLE 57

(Compound No. 1589)

1H-2- 1-Methyl-4-3-(imidazol-1-yl)propionyl!amino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)!amino!phenyl!carboxamide

In a mixed solvent of 3 ml of DMF and 3 ml of methanol, 0.20 g (0.40mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide was dissolved, followedby the addition of 0.50 ml of 1N hydrochloric acid. Using 0.10 g of 10%Pd/C (wet) as a catalyst, the resultant mixture was hydrogenated undernormal pressure so that it was converted to the corresponding aminoderivative. A solution of the amino derivative in DMF was stirred undera nitrogen gas atmosphere and ice-cooling. To the reaction mixture, 75μl (0.54 mmol; 1.3 equivalents) of triethylamine and a solution of3-(imidazol-1-yl)propionylimidazole in DMF, which had been prepared inadvance by dissolving 0.15 g (0.60 mmol) of3-(4-benzylpiperazinyl)propionic acid and 0.12 g (0.74 mmol) of CDI in 3ml of DMF and stirring the solution at room temperature for 2.5 hours,were added successively. The temperature of the resultant mixture wasallowed to rise back to room temperature, at which the mixture wasstirred for 4.5 hours. The reaction mixture was concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (ethyl acetate/IPA/water=6/2/1) and crystallized from ethylacetate, whereby 103 mg (0.17 mmol) of the title compound were obtainedas light brown crystals (yield: 42.5%).

m.p.>260° C.

IR(KBr)cm⁻¹ : 3287, 1636, 1518, 1328, 1239, 815

Elemental analysis for C₂₉ H₃₀ Cl₂ N₈ O₂.HCl: Calculated: C, 55.29; H,4.96; N, 17.79 Found: C, 54.94, H, 5.07; N, 17.81

EXAMPLE 58

(Compound No. 1604)

1H-2- 1-Methyl-4-furoylaminopyrrol-2-yl!benzimidazole-5- N- 3-N-ethyl,N-(2-chloroethyl)amino!phenyl!carboxamide

(Reaction 1)

3-Nitroacetanilide

To 10 g (72 mmol) of 3-nitroaniline, 10 ml (106 mmol) of aceticanhydride were added, followed by stirring. White crystals wereprecipitated with exotherm. After stirring for 10 minutes, ice water waspoured into the reaction mixture. The crystals were dissolved inchloroform, followed by washing successively with 1N hydrochloric acid,a saturated aqueous solution of sodium hydrogencarbonate and saturatedsaline. The organic layer was dried over anhydrous magnesium sulfate andthen the solvent was distilled out under reduced pressure. The residuewas washed with ethyl ether, whereby 11.6 g of white powder wereobtained (yield: 89%).

(Reaction 2)

3-Nitro-N-ethylaniline

To a solution of 8 g (44 mmol) of 3-nitroacetanilide in 200 ml of dryTHF, a solution of 5.5 ml (58 mmol) of borane dimethyl sulfide complexin 5 ml of THF was added, followed by stirring at 80° C. for 4 hours. Tothe reaction mixture, 3 ml (32 mmol) of borane dimethyl sulfide complexwere further added, followed by stirring at 80° C. for 3 hours. After 1Nhydrochloric acid was added to the reaction mixture until the solutionbecame uniform, the solvent was concentrated under reduced pressure. Tothe residue, a 10N aqueous solution of sodium hydroxide was added,followed by extraction with chloroform. The extract was washed withsaturated saline and then dried over magnesium sulfate. The solvent wasdistilled out under reduced pressure. The residue was purified bychromatography on a column (ethyl acetate/n-hexane=4/1), whereby 6.6 gof the title compound were obtained as brown powder (yield: 89%).

(Reaction 3)

3- N-Ethyl,N-(2-hydroxyethyl)!amino!nitrobenzene

In 40 ml of a 30% aqueous solution of acetic acid, 6.0 g (39.1 mmol) of3-(N-ethyl)aminonitrobenzene were dissolved, followed by the addition of11.5 g (261 mmol) of ethylene oxide under a nitrogen gas atmosphere. Theresultant mixture was stirred overnight at room temperature. Aftercompletion of the reaction, the reaction mixture was extracted withethyl acetate. The ethyl acetate layer was dried and concentrated,whereby 5.27 g of the title compound were obtained as a brown syrup(yield: 64.1%).

(Reaction 4)

3- N-Ethyl,N-(2-chloroethyl)!amino!nitrobenzene

In 50 ml of benzene, 3.0 g (14.3 mmol) of 3-N-ethyl,N-(2-hydroxyethyl)!amino!nitrobenzene were dissolved, followedby the addition of 4.1 g (29.2 mmol) of thionyl chloride. The resultantmixture was stirred at 60° C. for one hour. After completion of thereaction, the reaction mixture was concentrated and recrystallized fromethyl acetate/n-hexane, whereby 3.18 g of the title compound wereobtained as yellow powder (yield: 97%).

(Reaction 5)

3- N-Ethyl,N-2-chloroethyl)!aminoaniline

In 20 ml of concentrated hydrochloric acid, 640 mg (2.8 mmol) of 3-N-ethyl,N-(2-chloroethyl)!amino!nitrobenzene were dissolved, followed bythe addition of 2.5 g (11 mmol) of thionyl tin chloride dihydrate. Theresultant mixture was stirred under reflux for 2 hours. After completionof the reaction, ammonia water was added to the reaction mixture,followed by extraction with ethyl acetate. The ethyl acetate layer wasdried and concentrated, whereby a pale yellow syrup was obtained. To thesyrup, 4N hydrochloric acid/dioxane was added, whereby 624 mg of thetitle compound were obtained as a yellow syrup (yield: 82%).

(Reaction 6)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-N-ethyl,N-(2-chloroethyl)!amino!phenyl!!carboxamide

In 30 ml of DMF, 658 mg (2.3 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and624 mg (2.3 mmol) of 3- N-ethyl,N-(2-chloroethyl)!aminoaniline weredissolved. Under ice cooling, 530 μl (3.5 mmol) of DECP and 960 μl (6.9mmol) of triethylamine were added to the resultant solution by using asyringe. After ice cooling for two hours, the reaction mixture wasallowed to stand overnight at room temperature. After completion of thereaction, the reaction mixture was concentrated and the dark brownresidue in the form of syrup was purified by chromatography on a silicagel column (chloroform→2% methanol/chloroform). Relevant fractions werecollected and concentrated, whereby 428 mg of the title compound wereobtained as yellow powder (yield: 40%).

(Reaction 7)

1H-2-(1-Methyl-4-furoylaminopyrrolyl-2-yl)benzimidazole-5- N- 3-N-ethyl,N-(2-chloroethyl)!amino!phenyl!!carboxamide

In 10 ml of DMF and 10 ml of methanol, 200 mg (0.43 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-N-ethyl,N-(2-chloroethyl)!amino!phenyl!!carboxamide were dissolved. Tothe resultant solution, 250 mg of 10% Pd/C and 500 μl of 1N hydrochloricacid were added under a nitrogen stream, followed by hydrogenation atordinary temperature under normal pressure. After Pd/C was filtered off,the filtrate was concentrated to form a DMF solution. To the solution,120 μl of triethylamine and a solution of 56.2 mg (0.43 mmol) of furoylchloride in methylene chloride were added successively under icecooling. The resultant solution was allowed to stand overnight. Aftercompletion of the reaction, the reaction mixture was concentrated. Thedark brown residue in the form of syrup was purified by chromatographyon a silica gel column (chloroform/methanol=30/1), whereby 149 mg of thetitle compound were obtained as white powder (yield: 66%).

Elemental analysis for C₂₈ H₂₇ ClN₆ O₃ 1.5H₂ O: Calculated: C, 60.27; H,5.42; N, 15.06 Found: C, 60.51, H, 5.12; N, 15.41

EXAMPLE 59

(Compound No. 1480)

1H-2- 1-Methyl-4-(2-pyrrolcarboxamido)pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

To a solution of 40 mg (0.36 mmol) of 2-pyrrolecarboxylic acid in 10 mlof benzene, 0.1 ml (1.4 mmol) of thionyl chloride was added in areactor, followed by stirring under heat at 100° C. for 2 hours. Afterthe solvent was distilled out under reduced pressure, a small amount ofbenzene was added to the residue. Distillation was repeated twice underreduced pressure. The acid chloride so obtained was immediately providedfor use in the next reaction. In 10 ml of a 1:1 mixed solvent of DMF andmethanol, 150 mg (0.30 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)!amino!phenyl!!carboxamide were dissolved,followed by the addition of 150 mg of 10% Pd/C and 360 μl of 1Nhydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with a hydrogen gas, followed by stirring at room temperature for2 hours. After Pd/C was filtered off, the filtrate was concentrated toform a DMF solution. To the solution, 62 μl (0.45 mmol) of triethylamineand 2-pyrrolecarboxylic acid chloride, which had been synthesized inadvance, were successively added. The resultant mixture was stirred atroom temperature for one hour. The reaction mixture was added with 5 mlof methanol and was then allowed to stand overnight. The solvent wasdistilled out under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform/methanol=95/5),whereby 50 mg of the title compound were obtained as white powder(yield: 30%).

IR(KBr)cm⁻¹ : 3148, 1636, 1518, 1419, 812, 756

EXAMPLE 60

(Compound No. 1520)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a mixed solvent of 3 ml of DMF and 3 ml of methanol, 0.20 g (0.40mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved, followedby the addition of 0.45 ml of 1N hydrochloric acid. Using 0.10 g of 10%Pd/C (wet) as a catalyst, hydrogenation was conducted under normalpressure to obtain the corresponding amino derivative. A solution of theamino derivative in DMF was stirred under a nitrogen gas stream and icecooling. To the reaction mixture, 67 μl (0.48 mmol; 1.2 equivalents) oftriethylamine and a DMF solution of 3-(methylthio)propionylimidazole,which had been prepared by dissolving 0.06 g (0.50 mmol; 1.2equivalents) of 3-(methylthio)propionic acid and 95 mg (0.59 mmol; 1.4equivalents) of CDI in 3 ml of DMF, were added. The temperature of theresultant mixture was allowed to rise back to room temperature, at whichthe mixture was stirred for 4 hours. The reaction mixture was thenallowed to stand overnight, followed by concentration under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (chloroform/4% methanol) and crystallized from ethylacetate-ethyl ether, whereby 164 mg (0.29 mmol) of the title compoundwere obtained as light brown crystals (yield: 71.6%).

IR(KBr)cm⁻¹ : 3275, 1642, 1518, 1327, 813

Elemental analysis for C₂₇ H₃₀ Cl₂ N₆ O₂ S: Calculated: C, 56.54; H.5.27; N: 14.65, Cl: 12.36 Found: C, 56.12, H, 5.22; N, 14.30, Cl: 12.30

EXAMPLE 61

(Compound No. 1527)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-chloro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In 10 ml of a 1:1 mixed solvent of DMF and methanol, 201 mg (0.38 mmol)of 1H-2- 1-methyl-4-nitropyrrol-2-yl!benzimidazole-5- N- 3-chloro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved in areactor, followed by the addition of 200 mg of 10% Pd/C and 412 μl of 1Nhydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with a hydrogen gas, followed by stirring at room temperature for2 hours. After Pd/C was filtered off, the filtrate was concentrated toform a DMF solution. To the solution, 78 μl (0.56 mmol) of triethylamineand a solution of an active intermediate, which had been prepared inadvance by reacting 135 mg (1.12 mmol) of 3-(methylthio)propionic acidwith 182 mg (1.12 mmol) of CDI, in 5 ml of DMF were added and theresultant mixture was allowed to stand overnight. The solvent wasdistilled out under reduced pressure. The residue so obtained waspurified by chromatography on a silica gel column(chloroform/methanol=96/4). Further purification was conducted bychromatography on a silica gel column (ethyl acetate/n-hexane=3/1),whereby 45 mg of the title compound were obtained as white powder(yield: 20%).

EXAMPLE 62

(Compound No. 1528)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

(Reaction 1)

3-Fluoro-4- N,N-bis(2-hydroxyethyl)!aminonitrobenzene

In 4 ml of DMSO, 5.0 g (31.4 mmol) of 3,4-difluoronitrobenzene and 8.3 g(78.5 mmol) of diethanolamine were dissolved, followed by stirring underheat at 140° C. for one hour. After completion of the reaction, thereaction mixture was extracted with ethyl acetate. The ethyl acetatelayer was dried and concentrated. To the reddish brown syrup soobtained, n-hexane/ethyl acetate was added for crystallization, whereby6.93 g of the title compound were obtained as yellow powder (yield:90%).

(Reaction 2)

3-Fluoro-4- N,N-bis(2-chloroethyl)!aminonitrobenzene

In 12 ml of DMF, 1.3 g (5.32 mmol) of 3-fluoro-4-N,N-bis(2-hydroxyethyl)amino!nitrobenzene were dissolved, followed bythe dropwise addition of 1.47 g (12.8 mmol) of methanesulfonyl chlorideunder ice cooling. The resultant mixture was stirred under heat at 70°C. for one hour. After completion of the reaction, the reaction mixturewas concentrated. The yellow syrup so obtained was purified bychromatography on a silica gel column (chloroform). The relevantfractions were concentrated and then crystallized from n-hexane/ethylacetate, whereby 1.2 g of the title compound were obtained as yellowpowder (yield: 81%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-y)benzimidazole-5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In 10 ml of THF, 500 mg (1.78 mmol) of 3-fluoro-4-N,N-bis(2-chloroethyl)amino!nitrobenzene were dissolved. To theresultant solution, 200 mg of 10% Pd/C were added under a nitrogen gasatmosphere, followed by the addition of 450 μl of 4N hydrochloric acid.The resultant mixture was hydrogenated under normal pressure at ordinarytemperature. After Pd/C was filtered off, the filtrate was concentrated.To the concentrate, 510 mg (1.78 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid wereadded, followed by the successive addition of 468 μl (2.67 mmol) of DECPand 740 μl (5.34 mmol) of triethylamine. The resultant mixture wasallowed to stand overnight. After completion of the reaction, thereactant was concentrated. The dark brown syrup so obtained was purifiedby chromatography on a silica gel column (chloroform→chloroform+2%methanol), whereby 325.6 mg of the title compound were obtained asyellow powder (yield: 35%).

(Reaction 4)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In 10 ml of DMF and 10 ml of methanol, 150 mg (0.29 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved. To theresultant solution, 200 mg of 10% Pd/C were added under a nitrogen gasatmosphere, followed by the addition of 320 μl of 1N hydrochloric acid.Hydrogenation was conducted under normal pressure at ordinarytemperature. After Pd/C was filtered off, the filtrate was concentratedto form a DMF solution. To the solution, 49 μl (0.29 mmol) oftriethylamine and a solution of an active intermediate, which had beenprepared in advance by reacting 105 mg (0.87 mmol) of3-(methylthio)propionic acid with 141 mg (0.87 mmol) of CDI, in 5 ml ofDMF were added under ice cooling. The resulting solution was thenallowed to stand overnight. After completion of the reaction, thereaction mixture was concentrated. The residue in the form of brownsyrup was purified by chromatography on a silica gel column(chloroform/methanol=95/5). The concentrate was washed withn-hexane/chloroform, whereby 115 mg of the title compound were obtainedas pale yellow powder (yield: 67%).

Elemental analysis for C₂₇ H₂₉ Cl₂ FN₆ O₂ S.H₂ O: Calculated: C, 53.20;H, 5.13; N, 13.79 Found: C, 53.62; H, 4.95; N, 13.79

EXAMPLE 63

(Compound No. 1524)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In 10 ml of a 1:1 mixed solvent of DMF and methanol, 200 mg (0.39 mmol)of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved in areactor, followed by the addition of 150 mg of 10% Pd/C and 427 μl of 1Nhydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with a hydrogen gas, followed by stirring at room temperature for2 hours. After Pd/C was filtered off, the filtrate was concentrated toform a DMF solution. To the solution, 65 μl (0.46 mmol) of triethylamineand a solution of an active intermediate, which had been prepared inadvance by reacting 140 mg (1.17 mmol) of 3-(methylthio)propionic acidwith 200 mg (1.23 mmol) of CDI, in 5 ml of DMF were added, followed bystirring at room temperature for 3 hours. The reaction mixture wasallowed to stand overnight. The solvent was distilled out under reducedpressure. The residue so obtained was purified by chromatography on asilica gel column (chloroform/methanol=95/5), whereby 195 mg of thetitle compound were obtained as white powder (yield: 86%).

IR(KBr)cm⁻¹ : 3163, 1654, 1509, 1397, 1063, 805

EXAMPLE 64

(Compound No. 1530)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (102 mg; 0.20 mmol) wasdissolved in 10 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 100 mg of 10% Pd/C and 218 μl of 1Nhydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with a hydrogen gas, followed by stirring at room temperature for2 hours. After Pd/C was filtered off, the filtrate was concentrated toform a DMF solution. To the solution, 55 μl (0.39 mmol) of triethylamineand a solution of an active intermediate, which had been prepared inadvance by reacting 71 mg (0.59 mmol) of 3-(methylthio)propionic acidand 96 mg (0.59 mmol) of CDI, in 5 ml of DMF were added under icecooling. The reaction mixture was then allowed to stand overnight. Thesolvent was distilled out under reduced pressure. The residue soobtained was purified by chromatography on a silica gel column(chloroform/methanol=96/4), whereby 100 mg of the title compound wereobtained as white powder (yield: 86%).

EXAMPLE 65

(Compound No. 1529)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N-3-trifluoromethyl-4-(N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

(Reaction 1)

3-Trifluoromethyl-4- N,N-bis(2-hydroxyethyl)amino!nitrobenzene

2-Fluoro-5-nitrobenzotrifluoride (5.0 g; 23.9 mmol) and 6.0 g (57.1mmol) of diethanolamine were dissolved solved in 30 ml of DMSO, followedby stirring under heat at 140° C. for 5 hours. The reaction mixture wasextracted with ethyl acetate and the extract was then dried overmagnesium sulfate. The brown oil so obtained was purified bychromatography on a silica gel column (chloroform/ methanol=10/1),whereby 565 mg of the title compound were obtained as yellow powder(yield: 8%).

(Reaction 2)

3-Trifluoromethyl-4- N,N-bis(2-chloroethyl)!amino!nitrobenzene

3-Trifluoromethyl-4- N,N-bis(2-hydroxyethyl)amino!nitrobenzene (0.556 g;1.89 mmol) was dissolved in 5 ml of DMF. Methanesulfonyl chloride (0.52g; 4.53 mmol) was added to the resultant solution, followed by stirringunder heat at 70° C. for one hour. After completion of the reaction, thereaction mixture was concentrated. The brown syrup so obtained waspurified by chromatography on a silica gel column (chloroform), whereby434 mg of the title compound were obtained as yellow powder (yield:70%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-3-trifluoromethyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (375mg; 1.33 mmol) and 3-trifluoromethyl-4-N,N-bis(2-chloroethyl)amino!aniline hydrochloride, which had beenobtained by catalytic hydrogenation of a solution of 434 mg (1.31 mmol)of 3-trifluoromethyl-4- N,N-bis(2-chloroethyl)amino!nitrobenzene in 10ml of methanol by using Pd/C as a catalyst, were dissolved in 10 ml ofDMF, followed by cooling to 0° C. Under a nitrogen gas atmosphere, thereaction mixture was added with 320 μl (2.3 mmol) of triethylamine andthen with 220 μl (1.45 mmol) of DECP, followed by stirring for 30minutes as was. After stirring for further two hours at roomtemperature, the solvent was distilled out under reduced pressure. Theresidue was purified by chromatography on a silica gel column(chloroform/methanol=10/1), whereby 159 mg of the title compound wereobtained as yellow powder (yield: 32%).

(Reaction 4)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N-3-trifluoromethyl-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N-3-trifluoromethyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (116mg; 0.20 mmol) was dissolved in 8 ml of a 1:1 mixed solvent of DMF andmethanol in a reactor, followed by the addition of 100 mg of 10% Pd/Cand 224 μl of 1N hydrochloric acid under a nitrogen gas atmosphere. Thereactor was purged with a hydrogen gas, followed by stirring at roomtemperature for 2 hours. After Pd/C was filtered off, the filtrate wasconcentrated to form a DMF solution. To the solution, 60 μl (0.43 mmol)of triethylamine and a solution of an active intermediate, which hadbeen prepared in advance by reacting 73 mg (0.61 mmol) of3-(methylthio)propionic acid with 100 mg (0.62 mmol) of CDI, in 5 ml ofDMF were added under ice cooling. The resultant solution was stirred atroom temperature for 6 hours and was then allowed to stand overnight.The solvent was distilled out under reduced pressure. The residue soobtained was purified by chromatography on a silica gel column(chloroform/methanol=95/5), whereby 90 mg of the title compound wereobtained as white powder (yield: 69%).

EXAMPLE 66

(Compound No. 1601)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!benz-2-oxa-1,3-diazolyl!!carboxamide

(Reaction 1)

4- N,N-Bis(2-hydroxyethyl)amino!-7-nitrobenz-2-oxa-1,3-diazole

4-Chloro-7-nitrobenz-2-oxa-1,3-diazole (5.0 g; 25 mmol) and 6.6 g (63mmol) of diethanolamine were dissolved in 4 ml of DMSO. The resultantsolution was stirred under heat at 140° C. for 2 hours, followed byextraction with ethyl acetate. The solvent was distilled out underreduced pressure, whereby 5.8 g of the title compound were obtained asorange powder (yield: 87%).

(Reaction 2)

4- N,N-Bis(2-chloroethyl)amino!-7-nitrobenz-2-oxa-1,3-diazole

4- N,N-Bis(2-hydroxyethyl)amino!-7-nitrobenz-2-oxa-1,3-diazole (1.0 g;3.7 mmol) was dissolved in 10 ml of DMF, followed by the addition of 2ml (9.0 mmol) of methanesulfonyl chloride. The resultant mixture wasstirred under heat at 70° C. for one hour. The solvent was distilled outunder reduced pressure. The brown oil so obtained was purified bychromatography on a silica gel column (chloroform:methanol=97:3),whereby 917 mg of the title compound were obtained as orange powder(yield: 81%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!benz-2-oxa-1,3-diazolyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (243mg: 0.85 mmol) and 4-N,N-bis(2-chloroethyl)amino!-7-aminobenz-2-oxa-1,3-diazolehydrochloride, which had been obtained by catalytic hydrogenation of asolution of 300 mg (0.85 mmol) of 4-N,N-bis(2-chloroethyl)amino!-7-nitrobenz-2-oxa-1,3-diazole in 10 ml ofmethanol by using Pd/C as a catalyst, were dissolved in 5 ml of DMF,followed by cooling to 0° C. To the reaction mixture, 355 μl (2.6 mmol)of triethylamine and then 193 μl (1.3 mmol) of DECP were added under anitrogen atmosphere, followed by stirring for 30 minutes as was.Stirring was conducted for further 2 hours at room temperature. Thesolvent was distilled off under reduced pressure. The residue soobtained was purified by chromatography on a silica gel column(chloroform/methanol=10/1), whereby 175 mg of the title compound wereobtained as orange powder (yield: 38%).

(Reaction 4)

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!benz-2-oxa-1,3-diazolyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!benz-2-oxa-1,3-diazolyl!!carboxamide (169mg; 0.31 mmol) was dissolved in 10 ml of a 1:1 mixed solvent of DMF andmethanol in a reactor, followed by the addition of 150 mg of 10% Pd/Cand 342 μl of 1N hydrochloric acid under a nitrogen gas atmosphere. Thereactor was purged with a hydrogen gas, followed by stirring at roomtemperature for 2 hours. After Pd/C was filtered off, the filtrate wasconcentrated to form a DMF solution. To the solution, 52 μl (0.37 mmol)of triethylamine and a solution of an active intermediate, which hadbeen prepared in advance by reacting 112 mg (0.93 mmol) of3-(methylthio)propionic acid with 151 mg (0.93 mmol) of CDI, in 5 ml ofDMF were added under ice cooling. The reaction mixture was then allowedto stand overnight. The solvent was distilled out under reducedpressure. The residue so obtained was purified by chromatography on asilica gel column (chloroform/methanol=96/4). The solvent was distilledout under reduced pressure. The residue was dissolved in ethyl acetate,followed by the addition of ethyl ether to cause re-precipitation,whereby 89 mg of the title compound were obtained as orange powder(yield: 46%).

IR(KBr)cm⁻¹ : 3134, 1654, 1535, 1289, 811, 743

EXAMPLE 67

(I⁻ salt of Compound No. 1056)

2- N- 1-Methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (76 mg; 0.13 mmol) wasdissolved in 0.5 ml of 80% formic acid, 0.25 ml of acetic acid and 0.2ml of methyl iodide. The resultant solution was stirred at roomtemperature for 9 hours under shading and was then allowed to standovernight. The reaction mixture was added with methanol, followed byconcentration under reduced pressure. The concentrate was evaporatedwith ethanol and to the residue, IPA was added. The solid so obtainedwas collected by filtration, whereby 54 mg (0.075 mmol) of the titlecompound were obtained as a light brown hygroscopic solid (yield:58.1%). The filtrate was concentrated further and treated with ethylacetate, whereby 22 mg (0.031 mmol) of the title compound were obtained(yield: 23.7%). The total amount of the title compounds so obtained was76 mg (0.106 mmol; yield: 81.8%).

IR(KBr)cm⁻¹ : 3397, 1648, 1517, 1327, 814

Elemental analysis for C₂₈ H₃₃ Cl₂ IN₆ O₂ S: Calculated: C, 47.01; H,4.84; N, 11.75 Found: C, 46.97; H, 4.84, N, 11.78

EXAMPLE 68

(I⁻ salt of Compound No. 1076)

2- N- 1-Methyl-2- 5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!!phenyl!carboxamide (100 mg; 0.19 mmol) wasdissolved in 1 ml of 80% formic acid, 0.5 ml of acetic acid and 0.4 mlof methyl iodide. The resultant solution was stirred at room temperaturefor two nights under shading. After completion of the reaction, thereaction mixture was added with methanol and was evaporated withmethanol three times. The residue was washed with ethanol, whereby 100mg of the title compound were obtained as pale yellow powder (yield:98%).

Elemental analysis for C₂₈ H₃₂ Cl₂ FIN₆ O₂.H₂ O: Calculated: C, 44.75;H, 4.56; N, 11.18 Found: C, 44.60; H, 4.59; N, 10.83

EXAMPLE 69

(I⁻ salt of Compound No.1060)

2- N- 1-Methyl-2- 5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (40 mg; 0.068 mmol) wasadded to a mixed solvent of 240 μl of 80% of formic acid and 120 μl ofacetic acid. To the resultant solution, 210 μl of methyl iodide wereadded, followed by stirring at room temperature for 7 hours undershading. The reaction mixture was allowed to stand overnight. Methanolwas added and the solvent was distilled out under reduced pressure. Tothe residue, toluene was added. Distillation was repeated three timesunder reduced pressure. The residue was washed with IPA, whereby 35 mgof the title compound were obtained as pale yellow powder (yield: 70%).

IR(KBr)cm⁻¹ : 3254, 1648, 1510, 1307, 803, 744

EXAMPLE 70

(I⁻ salt of Compound No. 1079)

2- N- 1-Methyl-2- 5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (84 mg; 0.14 mmol) wasdissolved in a mixed solvent of 500 μl of 80% formic acid and 250 μl ofacetic acid. To the resultant solution, 210 μl of methyl iodide wereadded, followed by stirring at room temperature for 4 hours undershading. The reaction mixture was allowed to stand overnight. Methanolwas added and the solvent D was distilled out under reduced pressure.Toluene was added to the residue and the distillation was repeated threetimes under reduced pressure. The residue was washed with ethyl acetate,whereby 99 mg of the title compound were obtained as white powder(yield: 95%).

IR(KBr)cm⁻¹ : 3245, 1654, 1512, 1306, 802, 745

EXAMPLE 71

(Cl⁻ salt of Compound No. 1077)

2- N- 1-Methyl-2- 5- N- 3-trifluoromethyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumchloride

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N-3-trifluoromethyl-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (86mg; 0.13 mmol) was dissolved in a mixed solvent of 500 μl of 80% formicacid and 250 μl of acetic acid. To the resultant solution, 210 μl ofmethyl iodide were added, followed by stirring at room temperature forone hour under shading. The reaction mixture was allowed to standovernight. To the reaction mixture, further 210 μl of methyl iodide wereadded, followed by stirring at room temperature for 8 hours. Thereaction mixture was allowed to stand overnight. Methanol was added andthe solvent was distilled out under reduced pressure. Toluene was addedto the residue and the distillation was repeated twice under reducedpressure. The residue was dissolved in methanol and passed through anion-exchange column ("DOWEX" 1×8, Cl⁻ type), whereby iodine ions ascounter ions were exchanged by chlorine ions. The solvent was distilledout under reduced pressure. The residue so obtained was washed withmethanol, whereby 75 mg of the title compound were obtained as whitepowder (yield: 81%).

IR(KBr)cm⁻¹ : 3240, 1656, 1541, 1418, 1319, 1048, 747

EXAMPLE 72

(Cl⁻ salt of Compound No.1602)

2- N- 1-Methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!benz-2-oxa-1,3-diazolyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumchloride

1H-2-1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5-N- 4-N,N-bis(2-chloroethyl)amino!benz-2-oxa-1,3-diazolyl!!carboxamide (50 mg;0.081 mmol) was dissolved in a mixed solvent of 300 μl of 80% formicacid and 150 μl of acetic acid. To the resultant solution, 260 μl (4.2mmol) of methyl iodide were added, followed by stirring at roomtemperature for 7 hours under shading. The reaction mixture was allowedto stand for two nights. Methanol was added and the solvent wasdistilled out under reduced pressure. Toluene was added to the residueand the distillation was repeated twice under reduced pressure. Theresidue was dissolved in methanol and passed through an ion-exchangeresin ("DOWEX" 1×8, Cl⁻ type), whereby iodine ions as counter ions wereexchanged by chlorine ions. The solvent was distilled out under reducedpressure. The residue so obtained was washed with methanol, whereby 39mg of the title compound were obtained as orange powder (yield: 72%).

IR(KBr)cm⁻¹ : 3228, 1660, 1534, 1419, 1290, 813, 740

EXAMPLE 73

(Cl⁻ salt of Compound No. 1072)

2- N- 1-Methyl-2- 5- N- 3-chloro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumchloride

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-chloro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (40 mg; 0.066 mmol) wasdissolved in a mixed solvent of 240 μl of 80% formic acid and 120 μl ofacetic acid. To the resultant solution, 210 μl of methyl iodide wereadded, followed by stirring at room temperature for 8 hours undershading. The reaction mixture was allowed to stand overnight. Methanolwas added and the solvent was distilled out under reduced pressure.Toluene was added to the residue and the distillation was repeated twiceunder reduced pressure. The residue was dissolved in methanol and passedthrough an ion-exchange resin ("DOWEX" 1×8, Cl⁻ type), whereby iodineions as counter ions were exchanged by chlorine ions. The solvent wasdistilled out under reduced pressure. The residue so obtained was washedwith methanol/ethanol, whereby 38 mg of the title compound were obtainedas white powder (yield: 87%).

IR(KBr)cm⁻¹ : 3248, 1656, 1499, 1394, 1307, 826, 746

EXAMPLE 74

(Cl⁻ salt of Compound No. 1076)

2- N- 1-Methyl-2- 5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-ylpyrrol-4-yl!carbamoylethyl-dimethylsulfonium chloride

2- N- 1-Methyl-2- 5- N- 3-fluoro-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide (100 mg; 0.17 mmol) was dissolved in methanol. The solution wassubjected to chromatography on an anion exchange resin ("DOWEX" 1×8, Cl⁻type), whereby iodine ions as counter ions were exchanged by chlorineions. After elution, the residue was washed with methanol, whereby 20 mgof the title compound were obtained as white powder (yield: 19%).

EXAMPLE 75

(Cl⁻ salt of Compound No. 1060)

2- N- 1-Methyl-2- 5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumchloride

1H-2- 1-Methyl-4-3-(methylthio)propionylamino!pyrrol-2-yl!benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (100 mg; 0.17 mmol) wasdissolved in a mixed solvent of 600 μl of 80% formic acid and 300 μl ofacetic acid. To the resultant solution, 250 μl of methyl iodide wereadded, followed by stirring at room temperature for 6 hours undershading. The reaction mixture was allowed to stand overnight. Thereaction mixture was stirred at room temperature for further 10 hoursand was allowed to stand overnight again. Methanol was added and thesolvent was distilled out under reduced pressure. Toluene was added tothe residue and the distillation was repeated twice under reducedpressure. The residue was dissolved in methanol and passed through anion-exchange column ("DOWEX" 1×8, Cl⁻ type), whereby iodine ions ascounter ions were exchanged by chlorine ions. The solvent was distilledout under reduced pressure. The residue so obtained was washed withmethanol, whereby 60 mg of the title compound were obtained as whitepowder (yield: 55%).

IR(KBr)cm⁻¹ : 3248, 1648, 1512, 1307, 803, 742

EXAMPLE 76

(Cl⁻ salt of Compound No. 1079)

2- N- 1-Methyl-2- 5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl)pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumchloride

2- N- 1-Methyl-2- 5- N- 2-methyl-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide (50 mg; 0.068 mmol) was dissolved in methanol. The resultantsolution was subjected to chromatography on an ion-exchange column("DOWEX" 1×8, Cl⁻ type) to exchange iodine ions as counter ions tochlorine ions, whereby 34 mg of the title compound were obtained aswhite powder (yield: 78%).

IR(KBr)cm⁻¹ : 3247, 1654, 1509, 1307, 802, 745

EXAMPLE 77

(Compound No. 1904)

1H-2- 1-Methyl-4-(methylthioacetylamino)pyrrol-2-yl!benzimidazol-5- N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (150 mg; 0.30 mmol) wasdissolved in 10 ml of DMF and 10 ml of methanol, followed by theaddition of 200 mg of 10% Pd/C and 320 μl of 1N hydrochloric acid. Theresultant solution was hydrogenated under normal pressure at roomtemperature. After the Pd/C was filtered off, the filtrate wasconcentrated to form a DMF solution. To the solution, 50 μl (0.30 mmol)of triethylamine and a solution of an active intermediate, which hadbeen obtained in advance by reacting 96 mg (0.90 mmol) ofmethylthioacetic acid and 146 mg (0.90 mmol) of CDI, in 5 ml of DMF wereadded under ice cooling. The thus-obtained mixture was allowed to standovernight. The reaction mixture was then concentrated. The brown oil soobtained was purified by chromatography on a silica gel column(chloroform/methanol=95/5), followed by washing with ether/chloroform,whereby 101 mg of the title compound were obtained as pale yellow powder(yield: 59%).

IR(KBr)cm⁻¹ : 3274, 2960, 2918, 1647, 1558, 1517, 1326,

EXAMPLE 78

(I' salt of Compound 1336)

2- N- 1-Methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylmethyl-dimethylsulfoniumiodide

Dissolved in a mixed solvent of 0.5 ml of 80% formic acid and 0.25 ml ofacetic acid were 100 mg (0.19 mmol) of 1H-2-1-methyl-4-(methylthioacetylamino)pyrrol-2-yl!benzimidazol-5- N-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 0.4 ml of methyl iodide. The resultant mixture was stirredat room temperature for 4 days under shading. The reaction mixture soobtained was purified by chromatography on a gel filtration column("Sephadex LH-20", methanol) and then, washed with methanol, whereby68.5 mg of the title compound were obtained as white powder (yield:55%).

IR(KBr)cm⁻¹ : 3398, 1654, 1578, 1518, 1325, 816

EXAMPLE 79

(Compound No. 1944)

1H-2- 1-Methyl-4-(2-pyridylacetyl)aminopyrrol-2-yl!benzimidazol-5- N-(4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (150 mg; 0.30 mmol) wasdissolved in a mixed solvent of 10 ml of DMF and 10 ml of methanol,followed by the addition of 200 mg of 10% Pd/C and 320 μl of 1Nhydrochloric acid. The resultant solution was hydrogenated under normalpressure at room temperature. After the Pd/C was filtered off, thefiltrate was concentrated to form a DMF solution. To the solution, 50 μl(0.30 mmol) of triethylamine and a solution of an active intermediate,which had been obtained in advance by reacting 156 mg (0.90 mmol) of2-pyridylacetic acid hydrochloride and 146 mg (0.90 mmol) of CDI, in 5ml of DMF were added under ice cooling. The thus-obtained mixture wasallowed to stand overnight. The reaction mixture was then concentrated.The brown oil so obtained was purified by chromatography on a silica gelcolumn (chloroform/methanol=10/1), followed by washing withether/chloroform, whereby 107 mg of the title compound were obtained aspale yellow powder (yield: 61%).

IR(KBr)cm⁻¹ : 3270, 2958, 1647, 1594, 1518, 1327, 815

EXAMPLE 80

(Compound No. 1952)

1H-2- 1-Methyl-4-(4-pyridylacetyl)aminopyrrol-2-yl!benzimidazol-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a reactor, 300 mg (0.60 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved in 10 mlof a 1:1 mixed solvent of DMF and methanol, followed by the addition of200 mg of 10% Pd/C and 718 μl of 1N hydrochloric acid under a nitrogengas atmosphere. The reactor was purged with hydrogen gas, followed bystirring at room temperature for 2 hours. After the Pd/C was filteredoff, the filtrate was concentrated to form a DMF solution. To thesolution, 100 μl (0.72 mmol) of triethylamine and a solution of anactive intermediate, which had been prepared in advance by reacting 311mg (1.8 mmol) of 4-pyridineacetic acid with 291 mg (1.8 mmol) of CDI, in5 me of DMF were added and the resultant mixture was allowed to standovernight. The solvent was distilled out under reduced pressure. Theresidue so obtained was purified by chromatography on a silica gelcolumn (chloroform/methanol=10/1→8/2). The solvent was distilled underreduced pressure, followed by reprecipitation with methanol and ethylacetate, whereby 190 mg of the title compound were obtained as whitepowder (yield: 54%).

IR(KBr)cm⁻¹ : 3280, 1638, 1518, 1328, 815, 716

Elemental analysis for C₃₀ H₂₉ Cl₂ N₇ O₂.H₂ O: Calculated: C, 59.31; H,4.98; N, 16.14 Found: C, 59.31; H, 5.11; N, 16.04

EXAMPLE 81

(Compound No. 1424)

1H-2- 1-Methyl-4-(3-pyridylacetylamino)pyrrol-2-yl!benzimidazol-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

In a reactor, 400 mg (0.80 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved in 10 mlof a 1:1 mixed solvent of DMF and methanol, followed by the addition of300 mg of 10% Pd/C and 1.2 ml of 1N hydrochloric acid under a nitrogengas atmosphere. The reactor was purged with hydrogen gas, followed bystirring at room temperature for 2 hours. After the Pd/C was filteredoff, the filtrate was concentrated to form a DMF solution. To thesolution, 133 μl (0.95 mmol) of triethylamine and a solution of anactive intermediate, which had been prepared in advance by reacting 416mg (2.4 mmol) of 3-puridineacetic acid with 388 mg (2.4 mmol) of CDI, in5 ml of DMF were added and the resultant mixture was allowed to standovernight. The solvent was distilled out under reduced pressure. Theresidue so obtained was purified by chromatography on a silica gelcolumn (chloroform/methanol=95/5). The solvent was distilled underreduced pressure, followed by reprecipitation with methanol and ethylacetate, whereby 270 mg of the title compound were obtained as whitepowder (yield: 54%).

IR(KBr)cm⁻¹ : 3096, 1648, 1516, 1327, 814, 711

Elemental analysis for C₃₀ H₂₉ Cl₂ N₇ O₂.H₂ O: Calculated: C, 59.31; H,4.98; N, 16.14 Found: C, 59.19; H, 4.88; N, 15.83

EXAMPLE 82

(Cl⁻ salt of Compound No. 1440)

3- N- 1-Methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylmethyl!pyridiniumchloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazol-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (79 mg; 0.13 mmol) wasdissolved in 50 ml of acetone. To the solution, 5 ml of methyl iodidewere added, followed by stirring at room temperature for 2 days. Afterthe solvent was distilled out under reduced pressure, the residue waspurified by chromatography on a silica gel column (ethylacetate/IPA/water/acetic acid =3/2/1/0→6/4/2/1). The solid so obtainedwas dissolved in methanol and passed through an ion-exchange resin("DOWEX" 1×8, Cl⁻ type), whereby counter ions were exchanged by chlorineions. The ion-exchanged solution was purified further by chromatographyon a gel filtration column ("Sephadex LH-20", methanol), whereby 47 mgof the title compound were obtained as pale yellow powder (yield: 58%).

IR(KBr)cm⁻¹ : 3243, 1638, 1518, 1328, 816, 745

EXAMPLE 83

(Cl⁻ salt of Compound No. 1716)

2- N- 1-Methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-trimethylammoniumchloride

1H-2- 1-Methyl-4-3-(N,N-dimethylamino)propionylamino!pyrrol-2-yl!benzimidazol-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (150 mg; 0.25 mmol) wasdissolved in 5 ml of methanol. To the solution, 39 mg (0.37 mmol) ofsodium carbonate and 70 mg (0.56 mmol) of dimethyl sulfate were added,followed by stirring at room temperature for two nights. After thesolvent was distilled out under reduced pressure, the residue waspurified by chromatography on a silica gel column (ethylacetate/IPA/water/ acetic acid 3/2/1/0→6/4/2/1). The solid so obtainedwas dissolved in methanol and passed through an ion-exchange resin("DOWEX" 1×8, Cl⁻ type), whereby counter ions were exchanged by chlorineions. The ion-exchanged solution was purified further by chromatographyon a gel filtration column ("Sephadex LH-20", methanol), whereby 72 mgof the title compound were obtained as pale yellow powder (yield: 46%).

IR(KBr)cm⁻¹ : 3261, 1648, 1518, 1328, 817

EXAMPLE 84

(Compound No. 1522)

1H-2- 1-Methyl-4-3-(methylthio)propionyl!aminopyrrol-2-yl!benzimidazole-5- N- 2- 4-N,N-bis(2-chloroethyl)amino!phenyl!ethyl!!carboxamide

In a mixed solvent of 4 ml of DMF and 3 ml of methanol, 0.25 g (0.47mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2- 4-N,N-bis(2-chloroethyl)amino!phenyl!ethyl!!carboxamide was dissolved.Using 10% Pd/C (wet) as a catalyst, the resultant mixture washydrogenated under normal pressure so that it was converted to thecorresponding amino derivative. The solvent was concentrated and the DMFsolution so obtained was stirred under a nitrogen gas stream andice-cooling. To the reaction mixture, 75 μl (0.54 mmol; 1.1 equivalents)of triethylamine and a solution of 3-(methylthio)propionylimidazole,which had been prepared from 0.07 g (0.58 mmol) of3-(methylthio)propionic acid and 0.12 g (0.74 mmol; 1.3 equivalents) ofCDI, in 4 ml of DMF were added successively. The temperature of theresultant mixture was allowed to rise back to room temperature, at whichthe mixture was stirred for 4 hours. The reaction mixture was thenallowed to stand overnight, followed by concentration under reducedpressure. The residue so obtained was purified by chromatography on asilica gel column (chloroform/4% methanol) and crystallized from ethylether, whereby 0.19 g (0.32 mmol) of the title compound was obtained asreddish white crystals (yield: 67.2%).

m.p. 152°-155° C.

IR(KBr)cm⁻¹ ; 3270, 2925, 1618, 1542, 1519, 1349, 1303

EXAMPLE 85

(I⁻ salt of Compound No. 1058)

2- N- 1-Methyl-2- 5- N- 2- 4- N,N-bis(2-chloroethyl)amino!phenyl!ethyl!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide

1H-2- 1-Methyl-4-3-(methylthio)propionyl!aminopyrrol-2-yl!benzimidazole-5- N- 2- 4-N,N-bis(2-chloroethyl)amino!phenyl!ethyl!!carboxamide (0.10 g; 0.17mmol) was dissolved in 0.5 ml of 80% formic acid, 0.25 ml of acetic acidand 0.2 ml of methyl iodide. The resultant solution was allowed to standovernight at room temperature under shading. The reaction mixture wasthen concentrated under reduced pressure. The residue so obtained wassubjected to gel filtration ("Sephadex LH-20", methanol) and then,crystallized from ethyl ether, whereby 99 mg (0.13 mmol) of the titlecompound were obtained as reddish white amorphous powder (yield: 78.3%).

IR(KBr)cm¹ : 3414, 1618, 1543, 1347, 1308

EXAMPLE 86

(Compound No. 1005)

1H-2- 1-Methyl-4-(2-guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-methyl-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

(Reaction 1)

3-Methyl-4- N,N-bis(2-hydroxyethyl)amino!nitrobenzene

In 30 ml of DMSO, 4.0 g (25.8 mmol) of 2-fluoro-5-nitrotoluene and 7.0 g(67 mmol) of diethanolamine were dissolved. The resultant solution wasstirred under heat at 140° C. for 6.5 hours, followed by extraction withethyl acetate. The solvent was distilled out under reduced pressure. Theresidue so obtained was washed with ethyl acetate, whereby 5.2 g of thetitle compound were obtained as yellow powder (yield: 84%).

(Reaction 2)

3-Methyl-4- N,N-bis(2-chloroethyl)amino!nitrobenzene

To a solution of 2.0 g (8.3 mmol) of 3-methyl-4-N,N-bis(2-hydroxyethyl)amino!nitrobenzene in 20 ml of benzene, 3 ml (40mmol) of thionyl chloride were added. After the resultant mixture wasstirred under heat at 80° C. for 2 hours, the solvent was distilled outunder reduced pressure. The residue so obtained was purified bychromatography on a silica gel column (ethyl acetate/n-hexane=1/1),whereby 2.0 g of the title compound were obtained as yellow powder(yield: 92%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

A solution of 280 mg (0.98 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and3-methyl-4- N,N-bis(2-chloroethyl)amino!aniline hydrochloride, which hadbeen derived from its corresponding nitro compound, in 10 ml of DMF wascooled to 0° C. Under a nitrogen gas atmosphere, 320 μl (2.3 mmol) oftriethylamine and then 220 μl (1.45 mmol) of DECP were added to theresultant solution, followed by stirring for 30 minutes as was. Afterthe stirring was conducted for further two hours at room temperature,the solvent was distilled out under reduced pressure. The residue soobtained was purified by chromatography on a silica gel column(chloroform/methanol=10/1), whereby 159 mg of the title compound wereobtained as yellow powder (yield: 32%).

(Reaction 4)

1H-2- 1-Methyl-4-(2-guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-methyl-4- N,N-bis(2-chloroethyl)amino!phenyl)!carboxamidedihydrochloride

In a reactor, 150 mg (0.29 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved in 10 mlof a 1:1 mixed solvent of DMF and methanol, followed by the addition of120 mg of 10% Pd/C and 350 μl of 1N hydrochloric acid under a nitrogengas atmosphere. The reactor was purged with hydrogen gas. The resultantmixture was stirred at room temperature for 2 hours. After the Pd/C wasfiltered off, the filtrate was concentrated to form a DMF solution. Tothe solution, 49 μl (0.35 mmol) of triethylamine, 134 mg (0.87 mmol) ofguanidineacetic acid hydrochloride and 180 mg (0.87 mmol) of DCC wereadded successively under ice cooling, followed by stirring at roomtemperature for one hour. The reaction mixture was then allowed to standovernight. White powder was removed by filtration, followed byconcentration under reduced pressure. To the residue so obtained, a 4Nhydrochloric acid/dioxane solution was added and the resultant mixturewas concentrated under reduced pressure. The residue was washed withmethanol, whereby 70 mg of the title compound were obtained as yellowpowder (yield: 29%).

IR(KBr)cm⁻¹ : 3378, 1655, 1510, 1310, 1242, 806

EXAMPLE 87

(Compound No. 1260)

1H-2- 1-Methyl-4-4-(N,N-dimethylamino)butyrylamino!pyrrol-2-yl!benzimidazole-5- N-3-methyl-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (237 mg; 0.46 mmol) wasdissolved in 10 ml of a 1:1 mixed solvent of DMF and methanol in areactor, followed by the addition of 200 mg of 10% Pd/C and 1 ml of 1Nhydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with hydrogen gas. The resultant mixture was stirred at roomtemperature for 2 hours. After the Pd/C was filtered off, the filtratewas concentrated to form a DMF solution. To the solution, 77 μl (0.56mmol) of triethylamine, 230 mg (1.4 mmol) of N,N-dimethylaminobutyricacid hydrochloride and 285 mg (1.4 mmol) of DCC were added successivelyunder ice cooling, followed by stirring at room temperature for onehour. The reaction mixture was then allowed to stand overnight. Whitepowder was removed from the reaction mixture by filtration, followed byconcentration under reduced pressure. The residue so obtained waspurified by chromatography on a silica gel column (ethylacetate/IPA/water=5/2/1), whereby 60 mg of the title compound wereobtained as white powder (yield: 21%).

EXAMPLE 88

(Compound No. 1464)

1H-2-(1-Methyl-4-furoylaminopyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (250 mg; 0.50 mmol) wasdissolved in a mixed solvent of 10 ml of DMF and 10 ml of methanol,followed by the addition of 250 mg of 10% Pd/C and 500 μl of 1Nhydrochloric acid under a nitrogen gas stream. The hydrogenation wasconducted under normal pressure at room pressure. After the Pd/C wasfiltered off, the filtrate was concentrated to form a DMF solution. Tothe solution, 140 μl of triethylamine and a solution of 65.2 mg (0.50mmol) of furoyl chloride in methylene chloride were added successivelyunder ice cooling. The reaction mixture was then allowed to standovernight, followed by concentration under reduced pressure. The darkbrown residue so obtained in the form of oil was purified bychromatography on a silica gel column (chloroform/methanol=20/1),whereby 191 mg of the title compound were obtained as pale yellow powder(yield: 67%).

IR(KBr)cm⁻¹ : 3276, 2958, 1643, 1594, 1518, 1327, 814, 758

EXAMPLE 89

(Compound No. 2089)

1H-2- 1-Methyl-4- 4-N-ethyl,N-(2-chloroethyl)amino!benzoylamino!pyrrol-2-yl!benzimidazole-5-N- 4- N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

(Reaction 1)

4- N-Ethyl,N-(2-hydroxyethyl)amino!nitrobenzene

In 30 ml of DMSO, 5.0 g (35.4 mmol) of 4-fluoronitrobenzene and 6 g(67.3 mmol) of 2-(ethylamino)ethanol were dissolved. The resultantsolution was stirred under heat at 140° C. for 4 hours, followed byextraction with ethyl acetate. The solvent was distilled out underreduced pressure, followed by washing with ethyl acetate, whereby 6.3 gof yellow powder were obtained (yield: 85%).

(Reaction 2)

4- N-Ethyl,N-(2-chloroethyl)amino!nitrobenzene

To a solution of 3.0 g (14.3 mmol) of 4-N-ethyl,N-(2-hydroxyethyl)amino!nitrobenzene in 20 ml of chloroform, 2.1ml (28.8 mmol) of thionyl chloride were added. After the resultantmixture was stirred under heat at 80° C. for 2 hours, the solvent wasdistilled out under reduced pressure. The residue was purified bychromatography on a silica gel column (ethyl acetate/n-hexane=1/1),whereby 3.0 g of yellow powder were obtained (yield: 92%).

IR(KBr)cm⁻¹ : 2975, 1598, 1310, 1277, 1115, 825, 725

(Reaction 3)

4- N-Ethyl,N-(2-chloroethyl)amino!aniline hydrochloride

To a solution of 3.0 g (13.1 mmol) of 4-N-ethyl,N-(2-chloroethyl)amino!nitrobenzene in 70 ml of a concentratedhydrochloric acid, 10 g of tin chloride were added. The resultantmixture was refluxed under heat for 3 hours, followed by treatment withaqueous ammonia and extraction with chloroform. The solvent wasdistilled out under reduced pressure. A solution of 4N hydrochloricacid/dioxane was added to the residue, followed by washing with IPA,whereby 3.1 g of the powder were obtained (yield: 100%).

(Reaction 4)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide

A solution of 400 mg (1.40 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid and329 mg (1.40 mmol) of 4- N-ethyl,N-(2-chloroethyl)amino!anilinehydrochloride in 10 ml of DMF was cooled to 0° C. Under a nitrogen gasatmosphere, 400 μl (2.89 mmol) of triethylamine and then 350 μl (2.31mmol) of DECP were added to the resultant solution, followed by stirringfor 30 minutes as was. The reaction mixture was stirred for further 2hours at room temperature. The solvent was then distilled out underreduced pressure. The residue was purified by chromatography on a silicagel column (chloroform/methanol=10/1), whereby 240 mg of yellow powderwere obtained (yield: 37%).

(Reaction 5)

4- N-Ethyl,N-(2-hydroxyethyl)amino!benzonitrile

A solution of 10 g (82.6 mmol) of 4-fluorobenzonitrile and 15 g (0.17mmol) of 2-(ethylamino)ethanol in 30 ml of DMSO was stirred under heatat 140° C. for 3 hours, followed by extraction with ethyl acetate. Thesolvent was distilled out under reduced pressure, followed by washingwith ethyl acetate, whereby 6.9 g of white powder were obtained (yield:44%).

IR(KBr)cm⁻¹ : 3456, 2221, 1609, 1530, 1407, 1357, 1177, 1043, 822

(Reaction 6)

4- N-Ethyl,N-(2-chloroethyl)amino!benzonitrile

To a solution of 6.0 g (31.5 mmol) of 4-N-ethyl,N-(2-hydroxyethyl)amino!nitrobenzene in 50 ml of chloroform, 5ml (68.5 mmol) of thionyl chloride were added. After the resultantmixture was stirred under heat at 70° C. for 3 hours, the solvent wasdistilled out under reduced pressure. The residue so obtained waspurified by chromatography on a silica gel column (ethyl acetate),whereby 5.0 g of white powder were obtained (yield: 76%).

(Reaction 7)

4- N-Ethyl,N-(2-chloroethyl)amino!benzoic acid

To a solution of 2.5 g (12.0 mmol) of 4-N-ethyl,N-(2-chloroethyl)amino!benzonitrile in 25 ml of ethanol, 25 mlof concentrated hydrochloric acid were added, followed by reflux underheat for 12 hours. The reaction mixture was allowed to cool down. Sodiumcarbonate was then added to basify the solution, followed by washingwith chloroform. The water layer was acidified with concentratedhydrochloric acid and then extracted with chloroform. The solvent wasdistilled out under reduced pressure, followed by washing with IPA,whereby 1.1 g of white powder were obtained (yield: 40%).

(Reaction 8)

1H-2- 1-Methyl-4- 4-N-ethyl,N-(2-chloroethyl)amino!benzoylamino!pyrrol-2-yl!benzimidazole-5-N- 4- N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

To a solution of 166 mg (0.73 mmol) of 4-N-ethyl,N-(2-chloroethyl)amino!benzoic acid in 10 ml of benzene, 0.6 ml(8.2 mmol) of thionyl chloride was added, followed by stirring underheat at 90° C. for 1.5 hours. The solvent was distilled out underreduced pressure. A small amount of benzene was added to the residue,followed by distillation under reduced pressure. This operation wasrepeated twice. The acid chloride so obtained was immediately providedfor use in the next reaction. In 10 ml of a 1:1 mixed solvent of DMF andmethanol, 200 mg (0.43 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4- N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide were dissolved, followed bythe addition of 200 mg of 10% Pd/C and 520 μl of 1N hydrochloric acidunder a nitrogen gas atmosphere. The reactor was purged with hydrogengas, followed by stirring at room temperature for 2 hours. After thePd/C was filtered off, the filtrate was concentrated to form a DMFsolution. To the solution, 120 μl (0.87 mmol) of triethylamine and theacid chloride, which had been synthesized above, were added successivelyunder ice cooling. The resultant mixture was stirred at room temperaturefor one hour, followed by the addition of 5 ml of methanol. The solventwas distilled out under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform/ methanol=98/2),whereby 170 mg of the title compound were obtained as pale yellow powder(yield: 61%).

IR(KBr)cm⁻¹ : 3422, 1973, 1606, 1519, 1271, 816

Elemental analysis for C₂₈ H₂₇ Cl₂ N₇ O₂.1.5H₂ O: Calculated: C, 56.86;H, 5.11; N, 16.57 Found: C, 57.28; H, 4.91; N, 16.21

EXAMPLE 90

(Compound No. 1048)

1H-2- 1-Methyl-4-(2-guanidinoacetylamino)pyrrol-2-yl!benzimidazol-5- N-4-N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

1H-2-(1-Methyl-4-2-nitropyrrol-2-yl)benzimidazol-5- N-4-(N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide (150 mg: 0.32mmol) was dissolved in 10 ml of a 1:1 mixed solvent of DMF and methanolin a reactor, followed by the addition of 150 mg of 10% Pd/C and 353 μlof 1N hydrochloric acid under a nitrogen gas atmosphere. The reactor waspurged with hydrogen gas and the resultant mixture was stirred at roomtemperature for 2 hours. After the Pd/C was filtered off, the filtratewas concentrated to form a DMF solution. To the solution, 54 μl (0.39mmol) of triethylamine, 150 mg (0.98 mmol) of guanidineacetic acidhydrochloride and 199 mg (0.97 mmol) of DCC were added successivelyunder ice cooling, followed by stirring at room temperature for onehour. The reaction mixture was allowed to stand overnight. White powderwas removed by filtration, followed by concentration under reducedpressure. The residue so obtained was dissolved in methanol and to thesolution, a solution of 4N hydrochloric acid/dioxane was added.Concentration was conducted again under reduced pressure. The residuewas then washed with methanol, whereby 115 mg of the title compound wereobtained as yellow powder (yield: 63%).

IR(KBr)cm⁻¹ : 3153, 1664, 1549, 1398, 1324, 826

EXAMPLE 91

(Compound No. 1049)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazol-5- N- 3-N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazol-5- N- 3-N-ethyl,N-(2-chloroethyl)amino!phenyl!!carboxamide (200 mg: 0.43 mmol)was dissolved in 10 ml of DMF and 10 ml of methanol, followed by theaddition of 200 mg of 10% Pd/C and 500 μl of 1N hydrochloric acid undera nitrogen gas atmosphere. The hydrogenation was conducted at roomtemperature under normal pressure. After the Pd/C was filtered off, thefiltrate was concentrated to form a DMF solution. To the solution, 75 μlof triethylamine, 197 mg (1.3 mmol) of guanidine hydrochloride and 265mg (1.3 mmol) of DCC were added successively under ice cooling. Theresultant mixture was allowed to stand overnight. After the reaction,the reaction mixture was filtered and concentrated. The dark brown oilso obtained was purified by chromatography on a gel filtration column("Sephadex LH-20", methanol), whereby 136 mg of the title compound wereobtained as white powder (yield: 56%).

EXAMPLE 92

(Compound No. 1009)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-methoxy-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

(Reaction 1)

3-Methoxy-4-(N,N-bis(2-hydroxyethyl)amino!nitrobenzene

To a suspension of 5.0 g (29.7 mmol) of 2-methoxy-5-nitroaniline in 30ml of 30% acetic acid, 20.0 g of ethylene oxide were added dropwiseunder ice cooling, followed by stirring for one hour. The reactionmixture was stirred further at room temperature overnight, followed bystirring at room temperature for 2 hours while nitrogen gas was blowninto the mixture. Sodium bicarbonate was then added to neutralize thereaction mixture, followed by the addition of salt until saturation. Theresultant mixture was extracted with ethyl acetate. After the extractwas dried over magnesium sulfate, the solvent was distilled out underreduced pressure. The residue was purified by chromatography on a silicagel column (methylene chloride/ethyl acetate=1/1→0/1), whereby 500 mg ofyellow powder were obtained (yield: 6.6%).

(Reaction 2)

3-Methoxy-4- N,N-bis(2-chloroethyl)amino!nitrobenzene

To a solution of 0.48 g (1.9 mmol) of 3-methoxy-4-N,N-bis(2-hydroxyethyl)amino!nitrobenzene in 20 ml of benzene, 1 ml (14mmol) of thionyl chloride were added. After the resultant mixture wasstirred under heat at 90° C. for 3 hours, the solvent was distilled outunder reduced pressure. The yellow oil so obtained was purified bychromatography on a silica gel column (ethyl acetate/n-hexane=1/1),whereby 350 mg of yellow powder were obtained (yield: 64%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-methoxy-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a reactor, 144 mg (0.49 mmol) of 3-methoxy-4-N,N-bis(2-chloroethyl)amino!nitrobenzene were dissolved in a mixedsolvent of 10 ml of methanol and 2 me of tetrahydrofuran, followed bythe addition of 150 mg of 10% Pd/C under a nitrogen gas atmosphere. Thereactor was purged with hydrogen gas, followed by stirring at roomtemperature for one hour. After completion of the reaction, the reactorwas purged with nitrogen gas, followed by stirring for 30 minutes. The10% Pd/C was then filtered off. To the thus-obtained methanol solution,200 μl of a solution of 4N hydrochloric acid/dioxane were added, whereby3-methoxy-4- N,N-bis(2-chloroethyl)amino!aniline hydrochloride wereobtained. The hydrochloride was provided for use in the next reaction.In 5 ml of DMF, 200 mg (0.7 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid andthe 3-methoxy-4- N,N-bis(2-chloroethyl)amino!aniline hydrochloride weredissolved, followed by cooling to 0° C. To the resulting solution, 102μl (0.74 mmol) of triethylamine and then 112 μl (0.74 mmol) of DECP wereadded under a nitrogen gas atmosphere, followed by stirring for 20minutes as was. The reaction mixture was stirred at room temperature forfurther one hour and was then allowed to stand overnight. The solventwas distilled out under reduced pressure. The residue so obtained waspurified by chromatography on a silica gel column (ethylacetate/n-hexane=1/1), whereby 80 mg of yellow powder were obtained(yield: 31%).

(Reaction 4)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3-methoxy-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

In a reactor, 73 mg (0.14 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazol-5- N- 3-methoxy-4-N,N-bis(2-chloroethyl)amino!phenyl!carboxamide were dissolved in 10 mlof a 1:1 mixed solvent of DMF and methanol, followed by the addition of70 mg of 10% Pd/C and 151 μl of 1N hydrochloric acid under a nitrogengas atmosphere. The reactor was purged with hydrogen gas, followed bystirring at room temperature for 2 hours. After the Pd/C was filteredoff, the filtrate was concentrated to form a DMF solution. To thesolution, 23 μl (0.17 mmol) of triethylamine, 65 mg (0.42 mmol) ofguanidineacetic acid hydrochloride and 85 mg (0.41 mmol) of DCC weresuccessively added under ice cooling, followed by stirring at roomtemperature for one hour. The reaction mixture was allowed to standovernight. White powder was removed by filtration and the filtrate wasconcentrated under reduced pressure. To the residue so obtained, asolution of 4N hydrochloric acid/dioxane was added, followed byconcentration under reduced pressure. The residue was washed withethanol/IPA, whereby 55 mg of the title compound were obtained as yellowpowder (yield: 59%).

EXAMPLE 93

(Compound No. 1024)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-2-methyl-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

(Reaction 1)

2-Methyl-4- N,N-bis(2-hydroxyethyl)amino!nitrobenzene

In 8 ml of DMSO, 5.0 g (64.5 mmol) of 2-nitro-5-fluorotoluene and 8.2 g(78 mmol) of diethanolamine were dissolved. The resultant solution wasstirred under heat at 140° C. for 7 hours, followed by extraction withethyl acetate. After the solvent was distilled out under reducedpressure, the residue was washed with ethyl acetate, whereby 10.1 g ofyellow powder were obtained (yield: 65%).

(Reaction 2)

2-Methyl-4- N,N-bis(2-chloroethyl)amino!nitrobenzene

To a solution of 1.0 g (4.2 mmol) of 2-methyl-4-N,N-bis(2-hydroxyethyl)amino!nitrobenzene in 20 ml of benzene, 5 ml (69mmol) of thionyl chloride were added. The resultant mixture was stirredunder heat at 80° C. for 6 hours, the solvent was distilled out underreduced pressure. The residue so obtained was purified by chromatographyon a silica gel column (chloroform), whereby 735 mg of yellow powderwere obtained (yield: 64%).

(Reaction 3)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

In a reactor, 300 mg (1.1 mmol) of 2-methyl-4-N,N-bis(2-chloroethyl)amino!nitrobenzene were dissolved in a mixedsolvent of 5 ml of methanol and 2 ml of tetrahydrofuran, followed by theaddition of 200 mg of 10% Pd/C under a nitrogen gas atmosphere. Thereactor was purged with hydrogen gas, followed by stirring at roomtemperature for one hour. After completion of the reaction, the reactorwas purged with nitrogen gas, followed by stirring for 30 minutes. The10% Pd/C was then filtered off. To the thus-obtained methanol solution,400 μl of a solution of 4N hydrochloric acid/dioxane were added, whereby2-methyl-4- N,N-bis(2-chloroethyl)amino!aniline hydrochloride wasobtained. In 10 ml of DMF, 309 mg (1.1 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid andthe 2-methyl-4- N,N-bis(2-chloroethyl)amino!aniline hydrochlorideobtained above were dissolved, followed by cooling to 0° C. Under anitrogen gas atmosphere, 330 μl (2.4 mmol) of triethylamine and then 197μl (1.3 mmol) of DECP were added to the resultant solution, followed bystirring for 20 minutes as was. Stirring was conducted for further 15minutes at room temperature. The reaction mixture was then allowed tostand overnight. The solvent was distilled out under reduced pressure.The residue so obtained was purified by chromatography on a silica gelcolumn (ethyl acetate/n-hexane=1/1), whereby 329 mg of yellow powderwere obtained (yield: 59%).

(Reaction 4)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-2-methyl-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamidedihydrochloride

In a reactor, 100 mg (0.19 mmol) of1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 2-methyl-4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide were dissolved in 10 mlof a 1:1 mixed solvent of DMF and methanol, followed by the addition of90 mg of 10% Pd/C and 220 μl of 1N hydrochloric acid under a nitrogengas atmosphere. The reactor was purged with hydrogen gas, followed bystirring at room temperature for 2 hours. After the Pd/C was filteredoff, the filtrate was concentrated to form a DMF solution. To thesolution, 32 μl (0.23 mmol) of triethylamine, 89 mg (0.58 mmol) ofguanidineacetic acid hydrochloride and 120 mg (0.58 mmol) of DCC weresuccessively added under ice cooling, followed by stirring at roomtemperature for one hour. The reaction mixture was allowed to standovernight. White powder was removed by filtration and the filtrate wasconcentrated under reduced pressure. To the residue so obtained, asolution of 4N hydrochloric acid/dioxane was added, followed byconcentration under reduced pressure. The residue was washed withmethanol, whereby 84 mg of the title compound were obtained as yellowpowder (yield: 66%).

EXAMPLE 94

(Compound No. 1256)

1H-2- 1-Methyl-4-4-(N,N-dimethylamino)butyrylamino!pyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis-(2-chloroethyl)amino!phenyl!!carboxamide hydrochloride

Dissolved in a mixed solvent of 3 ml of DMF and 3 ml of methanol was0.28 g (0.55 mmol) of 1H-2-(1-methyl-4-nitropyrrol-2-yl)benzimidazole-5-N- 4- N,N- bis(2-chloroethyl)amino!phenyl!!carboxamide, followed by theaddition of 0.14 ml of 4N hydrochloric acid. Using 0.13 g of 10% Pd/C asa catalyst, the reactant was converted to the corresponding aminoderivative by hydrogenation under normal pressure. A DMF solution of theamino derivative was stirred under a nitrogen gas stream andice-cooling, to which 0.16 ml (1.15 mmol; 2.0 equivalents) oftriethylamine and a solution of 4-(N,N-dimethylamino)butyrylchloride inmethylene chloride, which had been prepared from 0.14 g (0.84 mmol) of4-(N,N-dimethylamino)butyric acid hydrochloride, were add successively.The resultant mixture was stirred, as was, for 2 hours and then allowedto stand overnight. The crystals were filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (ethyl acetate/IPA/water=6/2/1;performed twice in total) and was then crystallized from ether-IPA,whereby 0.14 g (0.23 mmol) of the title compound were obtained as palebrown crystals (yield: 41.3%).

IR(KBr)cm⁻¹ : 3421, 1647, 1636, 1541, 1521

ESI-mass spectrum: m/z (C₂₉ H₃₅ N₇ O₂ Cl₂) 583.22, Found: 583.85

EXAMPLE 95

(Compound No. 1488)

1H-2- 4-(4-aminobuturylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

(Reaction 1)

1H-2- 1-methyl-4-4-(benzyloxycarbonylamino)butyrylamino!pyrrol-2-yl!benzimidazole-5-(N-4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (0.20 g; 0.40 mmol) wasdissolved in a mixed solvent of 3 ml of DMF and 3 ml of methanol,followed by the addition of 0.1 ml of 4N hydrochloric acid. Using 0.14 gof 10% Pd/C as a catalyst, hydrogenation was conducted under normalpressure so that the reactant was converted to its corresponding aminoderivative. The DMF solution of the amino derivative was stirred under anitrogen gas stream and ice cooling, to which 60 μl (0.43 mmol; 1.08equivalents) of triethylamine and N-4-(benzyloxycarbonylamino)butyryl!imidazole, which had been preparedfrom 0.14 g (0.59 mmol; 1.5 equivalents) of4-(benzyloxycarbonylamino)butyric acid and 0.10 g (0.62 mmol; 1.5equivalents) of CDI in 3 ml of DMF, were added. The resultant mixturewas stirred, as was, for 4 hours and then allowed to stand overnight.The reaction mixture was concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column(chloroform/methanol=96/4) and crystallized from ethyl ether, whereby0.18 g (0.25 mmol) of the title compound were obtained as pale ocherouscrystals (yield: 63.7%).

m.p. 118°-121° C.

(Reaction 2)

1H-2- 4-(4-Aminobutyrylamino)-1-methylpyrrol-2-yl!benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2- 4-4-(Benzyloxycarbonylamino)butyrylamino!-1-methylpyrrol-2-yl!benzimidazole-5-N- 4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (0.15 g; 0.2 mmol)was suspended in methanol, followed by the addition of 60 μl (0.24 mmol)of 4N hydrochloric acid/dioxane. Using 0.07 g of 10% Pd/C as a catalyst,the resultant suspension was hydrogenated under normal pressure. Aftercompletion of the reaction was confirmed, the reaction mixture wasconcentrated under reduced pressure. The residue was added with 4Nhydrochloric acid/dioxane, followed by concentration. The concentratewas crystallized from IPA, whereby 0.10 g (0.17 mmol) of the titlecompound were obtained as yellow crystals (yield: 76.7%).

IR(KBr)cm⁻¹ : 3364, 3067, 1649, 1567, 1517, 1396, 1330, 1060, 818

EXAMPLE 96

(Compound No. 1536)

1H-2- 1-Methyl-4-(4-morpholinecarbonyl)aminopyrrol-2-yl!benzimidazole-5-N- 4- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (0.15 g; 0.30 mmol) wasdissolved in a mixed solvent of 3 ml of DMF and 4 ml of methanol,followed by the addition of 0.4 ml of 1N hydrochloric acid. Using 0.08 gof 10% Pd/C as a catalyst, hydrogenation was conducted under normalpressure so that the reactant was converted to its corresponding aminoderivative. The DMF solution of the amino derivative was stirred under anitrogen gas atmosphere and ice cooling, to which 0.10 ml (0.72 mmol;2.4 equivalents) of triethylamine and 50 μl (0.43 mmol; 1.4 equivalents)of 4-morpholinecarbonylchloride were added. The temperature of theresultant mixture was allowed to rise back to room temperature, at whichthe mixture was stirred for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform/methanol=92/8) andcrystallized from ethyl ether, whereby 0.1 g (0.17 mmol) of the titlecompound were obtained as reddish white crystals (yield: 57.0%).

IR(KBr)cm⁻¹ : 3421, 1636, 1518, 1256

Elemental analysis for C₂₈ H₃₁ N₇ O₃ Cl₂.H₂ O: Calculated: C, 55.82; H,5.52; N, 16.27 Found: C, 55.58; H, 5.39; N, 16.09

EXAMPLE 97

(Compound No. 1047)

1H-2- 1-Methyl-4-(guanidinoacetylamino)pyrrol-2-yl!benzimidazole-5- N-3- N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

(Reaction 1)

3- N,N-Bis(2-chloroethyl)amino!aniline hydrochloride

3- N,N-Bis(2-chloroethyl)amino!nitrobenzene (2.0 g; 7.6 mmol) wasdissolved in 35 ml of concentrated hydrochloric acid, followed by theaddition of 6.9 g (30.6 mmol; 4.0 equivalents) of tin(II) chloridedihydrate. The resultant mixture was stirred under heat for 1 hour overan oil bath controlled at 100° C. The reaction mixture was allowed tocool down to room temperature, followed by dilution with water. Thediluted solution was basified with concentrated aqueous ammonia and thenextracted twice with ethyl acetate. The extract was dried over sodiumsulfate and then concentrated under reduced pressure. The residue soobtained was added with 4N hydrochloric acid/dioxane and concentrated.The concentrate was then crystallized from a small amount ofmethanol/ether, whereby 1.97 g (7.3 mmol) of the title compound wereobtained as yellow crystals (yield: 96.1%).

m.p. 195°-201° C.

(Reaction 2)

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5-carboxylic acid (0.40g; 1.4 mmol) and 0.38 g (1.4 mmol; 1.0 equivalent) of 3-N,N-bis(2-chloroethyl)amino!aniline hydrochloride were suspended in 10ml of DMF, followed by stirring under a nitrogen gas stream and icecooling. To the reaction mixture, 0.60 ml (4.3 mmol, 3.1 equivalents) oftriethylamine and 0.32 ml (2.1 mmol; 1.5 equivalents) of DECP weresuccessively added. The resultant mixture was stirred, as was, for 3.5hours and the allowed to stand overnight. The reaction mixture was thenconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform/methanol=98/2),followed by crystallization from IPA-n-hexane, whereby 0.41 g (0.82 mol)of the title compound were obtained as yellow powder (yield: 58.4%).

(Reaction 3)

1H-2- 4-(guanidinoacetyl)amino-1-methyl-pyrrol-2-yl!benzimidazole-5- N-3-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide dihydrochloride

1H-2-(1-Methyl-4-nitropyrrol-2-yl)benzimidazole-5- N- 3-N,N-bis(2-chloroethyl)amino!phenyl!!carboxamide (0.20 g: 0.40 mmol) wasdissolved in a mixed solvent of DMF and methanol, followed by theaddition of 0.46 ml of 1N hydrochloric acid. Using 0.11 g of 10% Pd/C asa catalyst, hydrogenation was conducted under normal pressure so thatthe reactant was converted to its corresponding amino derivative. TheDMF solution of the amino derivative was stirred under a nitrogen gasstream and ice cooling, to which 64 μl (0.46 mmol; 1.1 equivalents),0.18 g (1.17 mmol; 2.9 equivalents) of guanidineacetic acidhydrochloride and 0.25 g (1.21 mmol; 3.0 equivalents) of DCC weresuccessively added. The temperature of the resultant mixture was allowedto rise back to room temperature, at which the mixture was stirred for 5hours. The reaction mixture was allowed to stand overnight. After thesolid so obtained was filtered off, the filtrate was concentrated underreduced pressure. The residue was purified by chromatography on a gelfiltration column ("Sephadex LH-20", methanol). Eluted fractions wereadded with 4N hydrochloric acid/dioxane, concentrated and then washedwith ethanol, whereby 0.14 g (0.21 mmol) of the title compound wereobtained as white crystals (yield: 53.2%).

m.p. >250° C.

IR(KBr)cm⁻¹ : 3154, 1657, 1608, 1547, 1497

Elemental analysis for C₂₆ H₂₉ N₉ O₂ Cl₂.2HCl.2.5H₂ O: Calculated: C,45.36; H, 5.27; N, 18.31; Cl, 20.60 Found: C, 45.67; H, 5.21; N, 18.50Cl, 20.73

EXAMPLE 98

(Cl⁻ salt of Compound No. 1056)

2- N- 1-Methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumchloride

In methanol, 80 mg of 2- N- 1-methyl-2- 5- N- 4-N,N-bis(2-chloroethyl)amino!phenyl!!carbamoyl!-1H-benzimidazol-2-yl!pyrrol-4-yl!carbamoylethyl-dimethylsulfoniumiodide (I⁻ salt of Compound No. 1056) were dissolved. The resultingsolution was subjected to ion-exchange chromatography ("DOWEX" 1×8, Cltype), whereby I⁻ ions as counter ions were exchanged by Cl⁻ ions. Theresulting solution was then purified by gel filtration ("SephadexLH-20"; methanol), whereby 45 mg of the target product were obtained aspale yellow powder (yield: 64.5%).

IR(KBr)cm⁻¹ : 3418, 1648, 1517, 1417, 1328, 1181, 815

Test 1

To investigate bonding of these compounds with DNA, changes in Tm(melting temperature) were measured. With respect of each of thesecompounds, the measurement was conducted by determining the differencebetween Tm measured when a citrated buffer solution of anA(adenine)-T(thymine) DNA copolymer was added with the compound and thatmeasured when the compound was not added. For the measurement, aspectrophotometer ("HITACHI U-3200 MODEL") was used and for temperaturecontrol, "HITACHI SPR-10 MODEL" was used. The results are presented inTable 5.

As a result, the pyrrolylbenzimidazole skeleton according to the presentinvention or a compound having the skeleton as its partial structure wasproved to have property to bond to DNA.

Table 5 Effects of Invention Compounds on Tm

                  TABLE 5                                                         ______________________________________                                        Effects of Invention Compounds on Tm                                                 Comp'd. No.                                                                           ΔTm(°C.)                                          ______________________________________                                               318     7                                                                      4      17                                                                    Distamycin                                                                            10                                                             ______________________________________                                    

Test 2

A description will next be made of antitumor activities of thesecompounds. Antitumor activities of representative compounds are shown inTable 6. Their antitumor activities were determined by measuring theirin vitro inhibition of proliferation of tumored cells. Namely, mouse B16melanoma cells were spread over a 96-well culture plate. One day later,each drug was applied. The melanoma cells were then incubated for 3 daysin 5% CO₂ at 37° C. Following the method reported in Cancer Res., 48,589-601(1988), the concentration of the drug required to induce 50%inhibition on the proliferation was determined. As a comparativeexample, the results obtained from the application of distamycin arealso shown.

                  TABLE 6                                                         ______________________________________                                        Antitumor Activity                                                                          50% Inhibition                                                  Compound      (μg/mL)                                                      ______________________________________                                          1           0.23                                                              2           0.25                                                              3           0.019                                                             4           0.04                                                              6           0.02                                                             13           0.01                                                             14           0.57                                                             15           0.057                                                            16           0.6                                                              129          0.18                                                             223          1.1                                                              247          2.6                                                              260          0.034                                                            305          4.2                                                              310          0.76                                                             318          19.8                                                             326          12.0                                                             336          0.24                                                             342          0.78                                                             342          0.045                                                            424          0.08                                                             438          42.8                                                            1001          0.53                                                            1003          0.018                                                           1004          0.047                                                           1005          0.65                                                            1009          2.31                                                            1013          0.34                                                            1017          0.78                                                            1024          0.586                                                           1042          3.49                                                            1047          0.0946                                                          1048          5.58                                                            1049          0.274                                                           1056          0.25                                                            1072          0.51                                                            1076 (I' salt 0.51                                                            1076 (Cl' salt)                                                                             0.45                                                            1077          0.29                                                            1208          2.05                                                            1256          4.67                                                            1260          3.1                                                             1464          0.033                                                           1480          0.16                                                            1488          2.85                                                            1520          0.33                                                            1524          0.6                                                             1528          0.22                                                            1536          0.53                                                            1585          0.1                                                             1589          0.41                                                            1590          0.53                                                            1592          0.61                                                            1604          0.43                                                            1617          0.12                                                            2001          0.005                                                           2089          0.0057                                                          Distamycin    36.0                                                            ______________________________________                                    

Test 3

In vivo antitumor activities of these compounds were also studied. P388leukemia cells (10⁶ cells/mouse) were intraperitoneally transplanted tofemale CDF₁ mice. One, five and nine days later, each compound wasintraperitoneally administered (at 1, 3 or 10 mg/kg) to the mice. As ablank test, 5% glucose was intraperitoneally administered at 10 ml/kg tomice. Based on the group of the mice in the blank test as a controlgroup, the effects of the individual drugs are shown in terms of ILS.The term "ILS" is represented by the following formula: ##EQU1##

When test animals survived 8 weeks after the administration, the numberof those survived was recorded without calculation of ILS. The resultsare shown in Table 7.

                  TABLE 7                                                         ______________________________________                                        Antitumor Activity in vivo                                                              Concentration        Survived                                                 administered         After 8 weeks/                                 Compound  (μg/mL)    ILS    Tested Animals                                 ______________________________________                                        1         1             38                                                    2         1             59     2/5 (3)                                        6         1             94                                                    13        1             123    3/5 (3)                                        305       10            22                                                    310       1             88                                                    1001      10            115                                                   2001      10            47                                                    ______________________________________                                    

The number in parentheses indicate the concentration of compoundcorresponds

Test 4

Prepared was a 1×10⁷ cells/ml suspension of Colon 26 mouse colon cancercells in HBSS (Hanks' Balanced Salt Solution). A 0.1 ml portion of thecell suspension was subcutaneously transplanted to a lateroabdominalpart of each female CDF₁ mouse. After the body weight of the mouse wasmeasured on the following day of the transplantation of the tumor, asolution of a compound (5% glucose solution containing 5% of "Tween 80")was administered into the caudal vein of the mouse. On day 15, a tumorwas excised and its weight was measured.

The percentage of the average tumor weight of each experiment group ascalculated by supposing that the average tumor weight of the controlgroup not administered with any drug was 100% was calculated as a T/Cvalue.

The results are presented in Table 8. Corresponding to each compoundnumber, its T/C value is shown. The number in parentheses indicates theconcentration of the drug when the T/C value was indicated.

                  TABLE 8                                                         ______________________________________                                        The results of Test 4                                                         table 8                                                                       Compound         T/C (%) (Concn.mg/Kg)                                        ______________________________________                                          1              29 (2)                                                       1001              7 (6)                                                       1003             41 (0.3)                                                     1005             20 (15)                                                      1009             29 (10)                                                      1013             58 (3)                                                       1017             30 (3)                                                       1024             61 (10)                                                      1056              1 (15)                                                      1256             60 (15)                                                      Adriamycin       40 (20)                                                      ______________________________________                                    

Advantages of the Invention

As is evident from the tests, the compounds according to the presentinvention act on DNA and are useful as anticancer agents.

We claim:
 1. A compound represented by the following chemical formula(1) or a pharmacologically acceptable salt thereof: ##STR3587## whereinX, Y and Z each independently means CH, N, NH, N(CHD)_(t) CH₃, S or Owith the proviso that X, Y and Z do not al have the same meaning at thesame time and t is an integer of 0-5, m and n are integers of 0-5, R₁and R₂ each independently means a hydrogen atom, a C₁₋₂₀ alkyl group, aC₁₋₁₀ haloalkyl group, a C₁₋₁₀ alkoxyl group, a hydroxyl group, a C₁₋₁₀alkylthio group, a substituted or unsubstituted amino group, asubstituted or unsubstituted ammonium group, a substituted orunsubstituted sulfonium group, a substituted or unsubstituted phenylgroup, a substituted or unsubstituted 5-membered heteroring; asubstituted or unsubstituted 6-membered heteroring, a substituted orunsubstituted fused heteroring substituted or unsubstituted amindinogroup, a substituted or unsubstituted guanidino group, an amino acidresidual group, or a group represented by the following chemical formula(2) ##STR3588## wherein R₃ means (CH₂)_(r) or (CH₂)_(r) O in which rstands for an integer of 0-5 and the O atom is located closer to thephenyl group, R₄ means a hydrogen atom, a C₁₋₁₀ alkyl group, a C₁₋₁₀alkoxyl group, a halogen atom, a trifluoromethyl group, a cyano group,an amidino group, a guanidino group, a carboxyl group or --COR₇ in whichR₇ means C₁₋₅ alkyl group, an alkylamino group which may be substitutedby a substituted amino group, an amino group which may be substituted bya substituted or unsubstituted phenyl group, or a substituted orunsubstituted benzylamino group, R₅ means a hydrogen atom, a C₁₋₁₀ alkylgroup, a C₁₋₁₀ alkyoxyl group, a halogen atom, or --(CH₂)_(p) N(R₈)₂ or--(CH₂)_(p) NR₈ R₉ in which p stand for an integer of 0-5 or R₄ or R₅may form a ring when R₄ and R₅ take mutually adjacent positions, R₆means a hydrogen atom, --(CH₂)_(p) N(R₈)₂ or --(CH₂)_(p) NR₈ R₉ whereinin each case of R₅ and R₆, R₈ means --CH₂ CH₂ W, R₉ means a C₁₋₅ alkylgroup or a mesyl group, W means a halogen atom, a hydroxyl group, amesyloxy group, a tosyloxy group or --OCOR₇ in which R₇ and p have thesame meanings as defined above.
 2. A compound according to claim 1,wherein the 5-membered ring containing X, Y and Z is selected from anyone of pyrrole, 1-methylpyrrole, imidazole, 1-methylimidazole, furan andthiophene.
 3. A compound or a pharmacologically acceptable salt thereofaccording to claim 2, wherein R₁ means a C₁₋₁₀ haloalkyl group or agroup represented by the chemical formula (2).
 4. A compound or apharmacologically acceptable salt thereof according to claim 2, whereinR₂ means a C₁₋₁₀ haloalkyl group or a group represented by the chemicalformula (2).
 5. A compound or a pharmacologically acceptable saltthereof according to claim 3, wherein R₂ means a C₁₋₁₀ haloalkyl groupor a group represented by the chemical formula (2).
 6. A compound or apharmacologically acceptable salt thereof according to claim 3, whereinR₂ means a substituted or unsubstituted amino, guanidino or amidinogroup.
 7. A compound or a pharmacologically acceptable salt thereofaccording to claim 6, wherein R₂ means an unsubstituted amino, guanidinoor amidino group.
 8. A compound or pharmacologically acceptable saltthereof according to claim 4, wherein R₁ means a substituted orunsubstituted amino, guanidino or amidino group.
 9. A compound orpharmacologically acceptable salt thereof according to claim 8, whereinR₁ means an unsubstituted amino, guanidino or amidino group.
 10. Acompound or pharmacologically acceptable salt thereof according to claim4, wherein R₁ means a substituted or unsubstituted ammonium or sulfoniumgroup.
 11. A compound or pharmacologically acceptable salt thereofaccording to claim 10, wherein R₁ is a trimethylammonium,N-methylpicoryl or dimethylsulfonium group.
 12. A compound orpharmacologically acceptable salt thereof according to claim 4, whereinR₁ means a C₁₋₁₀ alkylthio group.
 13. A pharmaceutical compositioncomprising as an active ingredient the compound or the pharmacologicallyacceptable salt thereof according to claim
 1. 14. An anticancercomposition comprising as an active ingredient the compound or thepharmacologically acceptable salt thereof according to claim
 1. 15. Anantiviral composition comprising as an active ingredient the compound orthe pharmacologically acceptable salt thereof according to claim
 1. 16.An antimicrobial composition comprising as an active ingredient thecompound or the pharmacologically acceptable salt thereof according toclaim
 1. 17. A process for preparing a compound represented by thechemical formula (1), which comprises reacting a compound represented bythe chemical formula (7) with a carboxylic acid derivative representedby the chemical formula (8): ##STR3589## wherein X, Y and Z eachindependently means CH, N, NH, N(CH₂)_(t) CH₃, S or O with the provisothat X, Y and Z do not all have the same meaning at the same time and tis an integer of 0-5, m and n are integers of 0-5, R₁ and R₂ eachindependently means a hydrogen atom, a C₁₋₂₀ alkyl group, a C₁₋₁₀haloalkyl group, a C₁₋₁₀ alkoxyl group, a hydroxyl group, a C₁₋₁₀alkylthio group, a substituted or unsubstituted amino group, asubstituted or unsubstituted ammonium group, a substituted orunsubstituted sulfonium group, a substituted or unsubstituted phenylgroup, a substituted or unsubstituted 5-membered heteroring, asubstituted or unsubstituted 6-membered heteroring, a substituted orunsubstituted fused heteroring, substituted or unsubstituted amidinogroup, a substituted or unsubstituted guanidino group, an amino acidresidual group, or a group represented by the chemical formula (2):##STR3590## wherein R₃ means (CH₂)_(r) or (CH₂)_(r) O in which r standsfor an integer of 0-5 and the O atom is located closer to the phenylgroup, R₄ means a hydrogen atom, a C₁₋₁₀ alkyl group, a C₁₋₁₀ alkoxylgroup, a halogen atom, a trifluoromethyl group, a cyano group, anamidino group, a guanidino group, a carboxyl group or --COR₇ in which R₇means a C₁₋₅ alkyl group, an alkylamino group which may be substitutedby a substituted or unsubstituted amino group, an amino group which maybe substituted by a substituted or unsubstituted phenyl group, or asubstituted or unsubstituted benzylamino group, R₅ means a hydrogenatom, a C₁₋₁₀ alkyl group, a C₁₋₁₀ alkoxyl group, a halogen atom, or--(CH₂)_(p) N(R₈)₂ or --(CH₂)_(p) NR₈ R₉ in which p stands for aninteger of 0-5, or R₄ and R₅ may form a ring when R₄ and R₅ takemutually adjacent positions, R₆ means a hydrogen atom, --(CH₂)_(p)N(R₈)₂ or --(CH₂)_(p) NR₈ R₉ wherein in each case of R₅ and R₆, R₈ means--CH₂ CH₂ W, R₉ means a C₁₋₅ alkyl group or a mesyl group, W means ahalogen atom, a hydroxyl group, a mesyloxy group, a tosyloxy group or--OCOR₇ in which R₇ and p have the same meaning as defined above.
 18. Apreparation process according to claim 17, wherein the 5-membered ringcontaining X, Y and Z is selected from any one of pyrrole,1-methylpyrrole, imidazole, 1-methylimidazole, furan and thiophene.